Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases Α, Δ and Ε in Saccharomyces Cerevisiae

Genetic networks required to coordinate chromosome replication by DNA polymerases α, δ and ε in Saccharomyces cerevisiae

Marion Dubarry1, Conor Lawless1, A. Peter Banks2, Simon Cockell3 and David Lydall1

1Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

2High Throughput Screening Facility, Newcastle Biomedicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

3Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

Corresponding author: David Lydall [email protected] Faculty of Medical Sciences, Framlington Place, Institute for Cell and Molecular Biosciences, Cookson Building (M2.022) Newcastle University, Newcastle, NE2 4HH

DOI: 10.1534/g3.115.021493 Figure S1

A R908G 1267 1463 1 376 719 794 T971A 1247 1468 exonuclease pol1-4 polymerase Zinc finger (no activity) G904D S1238G

B 2182 1 123 442 638 1097 2103 2222 pol2-12 exonuclease polymerase Zinc finger non-essential N-terminal domain E2195* essential C-terminal domain C 1009 1081 P367H 1143 482 555 979 1097 cdc2-2 exonuclease polymerase

N363D P603S Zinc finger Figure S1: DNA polymerase alleles used in this study A-C) Representation of the DNA polymerase defective alleles used (BY4741 background). Mutations were identified by sequencing and indicated in A) for Pol α, in B) for Pol ε and in C) for Pol δ. Conserved domains of DNA polymerases are shown (exonuclease (grey), polymerase (yellow) and zinc finger (brown)) and mutations are shown in orange. Pol α lacks exonuclease activity because the sequence of catalytic motifs in the Exo domains is destroyed (Pavlov and Shcherbakova 2010).

M. Dubarry et al. 2 SI CD A b a b a b a b a b a b a b a b a Photographs Photographs lyp1∆ his3∆ lyp1∆ elg1∆ lyp1∆ ctf18∆ lyp1∆ rad9∆ pol2-12 elg1∆ pol2-12 ctf18∆ pol2-12 rad9∆ pol2-12 his3∆ 30°C 36°C

Culture density (AU) Culture density (AU) 00.10.200.10.200.10.200.10.2 00.10.200.10.200.10.200.10.2 MDP=0 MDR=0 MDP=5.7 MDR=5.54 MDP=0 MDR=0 MDP=6.52 MDR=4.2 MDP=7.09 MDR=12.9 MDP=6.81 MDR=14.5 MDP=6.61 MDR=14.1 MDP=6.89 MDR=12.8 a bab a ab MDP=6.98 MDR=14.5 MDP=5.6 MDR=4.99 MDP=0 MDR=0 MDP=7.11 MDR=12.8 MDP=6.84 MDR=13.8 MDP=7.02 MDR=11.9 MDP=4.51 MDR=0.372 MDP=6.05 MDR=5.79 bab

5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 B b a b a b a b a b a b a b a b a Photographs Photographs cdc2-2 ctf18∆ cdc2-2 rad9∆ cdc2-2 elg1∆ cdc2-2 his3∆ pol1-4 ctf18∆ pol1-4 elg1∆ pol1-4 rad9∆ pol1-4 his3∆ 33°C 30°C

Culture density (AU) Culture density (AU) 0 0.1 0.2 0 0.1 0.2 0 0.1 0.2 0.1 0.2 0 0.1 0.2 0 0.1 0.2 0 0.1 0.2 0 0.1 0.2 MDP=6.89 MDR=4.88 MDP=0 MDR=0 MDP=0 MDR=0 MDP=6.87 MDR=8 MDP=0 MDR=0 MDP=5.85 MDR=8.93 MDP=0 MDR=0 MDP=7.18 MDR=5.82 bab ab ab ab MDP=0 MDR=0 MDP=0 MDR=0 MDP=6.95 MDR=5.41 MDP=6.95 MDR=4.93 MDP=0 MDR=0 MDP=4.52 MDR=3.66 MDP=4.51 MDR=0.183 MDP=6.99 MDR=6.44

5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 5e−45e−3 5e-2 Figure S2 Figure S2: Quantitative fitness analysis A) First eleven photographs of a QFA time course showing two representative replicates (a and b) of his3Δ, rad9Δ, ctf18Δ and elg1Δ gene deletions combined with lyp1Δ (control) at 30°C (left panel). QFA growth curves (linear on the left and logarithmic on the right) for each of the double-mutants (a and b) are presented in the left panel at 30°C for 2.5 days (right panel). Cell density of individual cultures was determined after image-analysis. The generalized logistic growth model is fitted to each culture density time-series. Fitness is defined as the product of the MDR and MDP values. B) As in A) but gene deletions were combined with pol1-4 mutation at 33°C. C) As in A) but gene deletions were combined with pol2-12 mutation at 36°C. D) As in A) but gene deletions were combined with cdc2-2 mutation at 30°C.

M. Dubarry et al. 3 SI Figure S3

A B Level of the Level of the GO hierarchy GO hierarchy

1 8 2 3 4 9 5 6 7 10 8 9 11 10 11 12 12

Level of the C GO hierarchy

DNA strandstrand hheteroduplexeteroduplex tetelomerelomere 8 DNADNA replicationreplication DDNANA rrecombinationecombination DDNANA rerepairpair elongationelongation formation mmaintenanceaintenance

DNADNA strandstrand elongationelongation recomrecombinationalbinational ddouble-strandouble-strand bbase-excisionase-excision nnon-recombinationalon-recombinational mitotic recombination 9 iinvolvednvolved repair break repair reparepairir repair inin DNA replicationreplication

ddouble-strandouble-strand ttelomereelomere mimitochondrialtochondrial bbreakreak repairrepair DNA ddamageamage 10 mmaintenanceaintenance ddouble-strandouble-strand via homolohomologousgous chcheckpointeckpoint vviaia recombinationrecombination bbreakreak repairrepair rrecombinationecombination

mmitochondrialitochondrial ddouble-strandouble-strand mmitoticitotic G1/SG1/S ddouble-strandouble-strand bbreakreak repairrepair GG11 DNA damage mmitoticitotic DNA 11 transtransitionition bbreakreak repairrepair viviaa break-inducedbreak-induced ccheckpointheckpoint damage checkpoint ccheckpointheckpoint viviaa hhomologousomologous repreplicationlication rrecombinationecombination

mmitoticitotic G1G1 iintra-Sntra-S DNA DNA ddamageamage 12 damage checkpoint ccheckpointheckpoint Figure S3: Use of the GOrilla visualisation tool used to identify the enriched GO terms A) A screen shot of enriched GO terms identified by GOrilla for negative genetic interaction with Pol δ mutation. The lists of enriched GO terms with the three defective DNA polymerase mutants are shown in Tables S3-5. B-C) We filtered the results (Figure 1D-F) to include enriched GO terms that annotated more than one and less than 250 genes. Then, the list was filtered to include only the last terms (black boxes) of any branch ranked at least at the eighth level (dashed box) of the GO hierarchy. The GOrilla database version was updated on May 30, 2015.

M. Dubarry et al. 4 SI Figure S4 Figure S4: DIXY illustrates rrm3Δ and sgs1Δ genetic interactions with Pol ε A-C) Snapshot of DIXY web page. Static scatter plots exported from DIXY shows the mean fitness of rrm3Δ and sgs1Δ mutants in pol2-12 screen versus lyp1Δ control screen.

M. Dubarry et al. 5 SI Figure S5

A B 120 0˚C) 3 Fitness (28˚C)

cdc13-1 HU 100mM Fitness ( 0 20406080100 0 100 200 300

0 20406080100120 0 100 200 300 Control Fitness (30˚C) Control Fitness (30˚C) CDMre11 complex ● mre11Δ rad50Δ Distance (D) to the target mutant: xrs2Δ RAD24 DRank Description

RAD24 0 1 Checkpoint protein, 80 clamp loader of the Rad17-Mec3-Ddc1 RAD17 9.8 2 Checkpoint protein, forms a clamp with Ddc1 and Mec3

Mean fitness DDC1 17.4 3 Checkpoint protein,

40 forms a clamp with Rad17 and Mec3 ● RAD9 51.8 4 DNA damage checkpoint protein

20 ●

● ● ● ● 0 60 100 120

E bre1∆ ipp1-d ylr339c-d F rad57∆ ● ncb2-d ● shr3-d ● caf40∆ smi1∆ 120 120 rad52∆ pol32∆ ● htz1∆ lea1∆

● 80 80

● ● ●● Mean fitness Mean fitness 40 40

● 20 20 ●● ● ● ● ● ● 0 60 100 0 60● ●● 100 ●

α HU HU Pol Pol δ Pol ε Pol α Pol δ Pol ε Controlcdc13-1 Controlcdc13-1

Figure S5: Fitness profiles of regulators of DNA replication A) QFA fitness plot comparing cdc13-1 strains at 28°C with a lyp1Δ control strain at 30°C. Positive (blue upward triangles), negative (red downward triangles) and neutral (grey dot) genetic interactions are presented. The solid grey line is a linear regression through all points and the dashed line is the line of equal fitness. B) QFA Fitness plot comparing mutants from the deletion library growing on complete synthetic media (CSM) supplemented with 100mM HU with strains growing on CSM (Andrew et al. 2013). C) Fitness profiles of gene deletions affecting mre11Δ, rad50Δ and xrs2Δ (Mre11 complex). D) List of the top four gene deletions/DAmP mutations that show similar profiles to rad24Δ when combined with control (lyp1Δ), cdc13-1, pol1-4, pol2-12 and cdc2-2 mutations and in presence of 100mM HU. E-F) Fitness profiles of yfgΔ-d that negatively affect Pol α, Pol δ and Pol ε mutations (Table 1). E) Fitness profiles of yfgΔ-d that negatively affect the fitness of cdc13-1 mutants and the three DNA polymerase mutants. F) Fitness profiles of yfgΔ-d that do not affect the fitness of cdc13-1 mutants.

M. Dubarry et al. 6 SI Figure S6

A B C rad55∆ pri1-d rsc8-d ● rad51∆ ● pri2-d ctf4∆ 120 rad54∆

80 ● ● ●

● ● Mean fitness 40 ● ●

● 20

● ● ● 0 60 100

HU HU HU Pol α Pol δ Pol ε Pol α Pol δ Pol ε Pol α Pol δ Pol ε Controlcdc13-1 Controlcdc13-1 Controlcdc13-1

Figure S6: Fitness profiles of regulators of Pol δ and Pol α defective strains A) Fitness profiles of rad51Δ, rad54Δ, rad55Δ mutations across the screens. B) Fitness profiles of pri1-d and pri2-d mutations across the screens. C) Fitness profiles of rsc8-dΔ and ctf4Δ mutations across the screens.

M. Dubarry et al. 7 SI Figure S7

A B C ctf18∆ kar3∆ swd3∆ :::mrc1∆ mup1∆ elg1∆ cac2∆ cac1∆ yml102c-a∆ ino2∆ ● cac2∆ cdc73∆ mrc1∆ elp6∆ ctf4∆ ctf8∆ ylr311c∆ erv14∆ rpl43a∆ hht1∆ vps72∆ rlf2∆ hir3∆ hir2∆ 80 ● ● ● Mean fitness ● 40 ●

● 20 0 60 100 120

HU HU HU Pol α Pol δ Pol ε Pol α Pol δ Pol ε Pol α Pol δ Pol ε Controlcdc13-1 Controlcdc13-1 Controlcdc13-1 Figure S7: Fitness profiling helps to identify mutants that function in same pathways A) Fitness profiles for ctf18Δ and the top ten closest fitness profiles to elg1Δ in combination with control, cdc13-1, pol1-4, pol2-12 and cdc2-2 mutations and in presence of 100mM HU. B) As in A) but showing the top ten closest fitness profiles to elg1Δ. C) Fitness profiles for rlf2Δ (cac1Δ), cac2Δ (CAF-1 complex) and, hir2Δ and hir3Δ (HIRA complex) across the screens.

M. Dubarry et al. 8 SI Table S1: Strains used in this study

Strain Background ♯ Genotype Source DLY7388 BY4741 MATα lyp1::HphMX::LEU2::NatMX can1Δ::STE2pr-Sp_his5 This work DLY8094 BY4741 MATα LEU2::pol1-4::HphMX lyp1::NatMX can1Δ::STE2pr-Sp_his5 This work DLY8095 BY4741 MATα lyp1::LEU2-NatMX::pol2-12::HphMX can1Δ::STE2pr-Sp_his5 This work DLY8096 BY4741 MATα LEU2::cdc2-2::HphMX lyp1::NatMX can1Δ::STE2pr-Sp_his5 This work DLY8205 BY4741 MATα LEU2::cdc13-1::HphMX lyp1::NatMX can1Δ::STE2pr-Sp_his5 This work

♯BY4741 MATa or MATα his3Δ1 leu2Δ0 LYS2 met15Δ0 ura3Δ0

M. Dubarry et al. 9 SI Table S2 List of enhancers and suppressors of the DNA polymerase mutants (q<0.05)

Negative interactions Positive interactions

Pol α (pol1-4) AIM29 ALT1 APQ12 ASF1 ATG3 BDF2 BMH1 BRE1 BUD21 BUD28 CAF40 ALD3 ARA1 CHK1 CKB1 EMI5 EXO1 GPH1 HIS3 IRC14 NAT1 PGM2 CHD1 CIK1 CLA4 CSM3 CTF18 CTF4 CTF8 DDC1 DOT1 EAP1 ELC1 ELP6 PIB2 PNG1 PRM4 PUF6 RTT107 SAC7 TEM1 TOS3 UBP3 VPS60 FRS2 GIM4 GPB2 HDA3 HIR3 HPC2 HTZ1 IES5 IMP2' IPP1 LEA1 LSM6 YDL109C YDR262W YPK3 YPS6 ZRG8 LSM7 MF(ALPHA)1 MRC1 MTC1 MTC4 MTC6 MUP1 NCB2 NHP10 NHP2 NMD2 NST1 PAT1 PBY1 PET20 POL32 PPH21 PSY1 PUS7 RAD17 RAD24 RAD50 RAD52 RAD57 RAD9 REI1 RIF1 RPB7 RPC11 RPL14A RPL31B RPS0B RPS1B RPS20 RPS4A RPS9B RRD1 RRD2 RSC8 RTF1 RTT10 SGS1 SHR3 SIS2 SKO1 SMI1 SOK1 SOK2 SPE1 SPN1 SPT2 SRS2 STI1 SUI2 SWC5 SWD1 SWD3 TCO89 TEN1 TIF5 TIM10 TIM50 TPK3 TPT1 TRM11 UBA4 UPF3 VMS1 VPS63 XRS2 YBR099C YBR100W YDR269C YGL042C YJR087W YKE2 YKL069W YKL075C YLR339C YLR374C YMD8 YMR166C YMR245W YNL171C YNL235C YOL134C YPD1 YPL205C YPR050C YPR153W YPT6 :::MRC1

Pol δ (cdc2-2) BMH1 BRE1 CAF40 CFD1 DDC1 GPI15 HTZ1 INO2 INP52 IPP1 LEA1 LGE1 NCB2 NMD2 PKR1 PMR1 POL32 PRE8 PRI1 RAD17 RAD24 RAD50 RAD51 RAD52 RAD54 RAD55 RAD57 RAD9 RFC5 RMI1 SAD1 SHR3 SMI1 SPE1 TEN1 XRS2 YDR269C YLR339C YNL011C

Pol ε (pol2-12) AIM4 ARC18 ARP4 ARP6 ASF1 ATG21 ATO2 AZF1 BEM1 BET3 BFA1 BPH1 AIM14 ALG6 ALG7 APC4 ARO2 ARV1 ATG16 BAG7 BRP1 BRX1 BTN2 BRE1 BRE2 BUB2 BUD27 CAF40 CAT5 CDC21 CDC33 CHK1 CHS5 CKB1 BTS1 CIA1 DAS2 DBF2 DBP3 EIS1 ERP6 ERV25 FIN1 FLC2 FLC3 CKB2 CLB2 CLB5 CSM3 CTF18 CTF8 DCC1 DCR2 DDC1 DEG1 DFG16 DIA2 GCN1 GEP7 GLO2 GPI15 GUT2 HEM13 HEM3 HFD1 HOM2 HUL5 DPB11 DPB2 DPB3 DPH2 DPH5 DPH6 DST1 ELF1 ELP3 EPS1 ERG3 ESBP6 ICP55 IRC5 IRC7 MAF1 MCM3 MDS3 MMS2 MRT4 NDE1 NOP1 ETP1 GCS1 GET3 GIM3 GIM4 GPB1 GYP1 HCR1 HDA1 HDA3 HIR2 HOS2 NOP56 NTH1 ORM1 PCF11 PDC1 PDX1 PEX32 PHO5 PLB1 PML1 HPC2 HTZ1 IES5 ILM1 INP52 IPK1 IPP1 JJJ3 LAP2 LEA1 LGE1 LSM1 LSM7 PPT1 PRE2 PRP11 PRP38 PUF6 RAD10 RCK1 RGR1 RIS1 RKM2 LSP1 LTE1 MID1 MIT1 MMS22 MRC1 MRL1 MRN1 MTC1 MTC4 NCB2 NGL2 RPA43 RPC17 RPC19 RPL13A RPL16A RPL23A RPL24B RPL29 NHP10 NOP4 NPR3 NST1 NUP133 NUP188 PAT1 PCP1 PER1 PET130 PKP1 RPL2A RPL35B RPL37B RPL9A RPN12 RPN14 RPN6 RPN7 RPP1B POL32 PPH21 PRE9 PSF1 PSF2 RAD17 RAD24 RAD50 RAD52 RAD57 RAD9 RPS10A RPS17B RPT3 RTG2 SAP4 SCW11 SDS3 SEC20 SGF73 SIP5 RIM101 RIM13 RIM21 RIM8 RIM9 RRD2 RRM3 RRN9 RTF1 RXT3 SAC3 SLX9 SNM1 SPO20 SPT21 SSF1 SUP45 SWI4 TAF12 TFA2 TFB4 TIF6 SAD1 SAF1 SAP190 SET3 SGF29 SHE1 SHE4 SHR3 SIF2 SIR1 SIW14 SLT2 TOM22 TPA1 TPC1 TPP1 TVP23 UBP3 VID30 VTI1 YCL022C SMI1 SNT1 SNX3 SOH1 SOK2 SPN1 SRB2 SRN2 SRS2 SSO2 SWC5 SWD1 YDR161W YDR537C YFR035C YGL036W YGL109W YGL117W SWD3 SWF1 SWR1 TCO89 TIF5 TIM50 TRR2 TRS20 TRS85 TUM1 UBA4 YGL118C YGL159W YGL165C YGL176C YGR026W YGR051C UME6 URM1 VAC8 VAM10 VHS3 VID22 VIP1 VMS1 VPS13 VPS17 VPS21 YGR283C YHR049C-A YHR202W YIP4 YKL177W YML102C-A VPS29 VPS30 VPS5 VPS55 VPS60 VPS63 VPS71 VPS8 XRN1 XRS2 YMR034C YMR144W YMR196W YOL035C YPD1 YPR142C YRB1 YDR090C YGL042C YGL046W YGR122W YGR237C YJL169W YLR339C YNL235C YOL050C YPL205C YSC83 YSP1

M. Dubarry et al. 10 SI Table S3 Gene Ontology analysis of the genetic interactions identified with Pol α (pol1-4) mutation

Gene Ontology analysis was performed using Gorilla (Eden et al. 2009), last update May 2015 The GO term and their description are listed. The p-value, the False Discovery Rate (FDR) q-value and the enrichment (defined as follows: N is the total number of genes, B is the total number of genes associated with a specific GO term, n is the number of genes in the top of the user's input list or in the target set when appropriate, b is the number of genes in the intersection. Enrichment = (b/n) / (B/N)) are shown for each GO term and hits with p-values of less than 0.01 were included. Results are listed beginning with GO categories with the highest enrichment.

N.B. No GO terms were enriched using the positive genetic interactions as a list.

Cellular processes

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value GO:0031573 intra-S DNA damage checkpoint 6.05E-09 9.32E-07 29.72 (4320,8,109,6) DOT1 RAD9 MRC1 SGS1 DDC1 BRE1 GO:0044783 G1 DNA damage checkpoint 6.14E-05 3.01E-03 29.72 (4320,4,109,3) DOT1 RAD9 BRE1 GO:2000756 regulation of peptidyl-lysine acetylation 1.51E-04 6.50E-03 23.78 (4320,5,109,3) HIR3 ASF1 CHD1 negative regulation of DNA-dependent DNA GO:2000104 1.51E-04 6.43E-03 23.78 (4320,5,109,3) CSM3 MRC1 CHD1 replication GO:1901983 regulation of protein acetylation 1.51E-04 6.37E-03 23.78 (4320,5,109,3) HIR3 ASF1 CHD1 GO:0035065 regulation of histone acetylation 1.51E-04 6.31E-03 23.78 (4320,5,109,3) HIR3 ASF1 CHD1 GO:0070911 global genome nucleotide-excision repair 1.51E-04 6.25E-03 23.78 (4320,5,109,3) DOT1 RTF1 ELC1 GO:0044773 mitotic DNA damage checkpoint 4.35E-08 3.91E-06 23.78 (4320,10,109,6) DOT1 RAD9 MRC1 DDC1 SGS1 BRE1 DNA replication-independent nucleosome GO:0006336 2.96E-04 1.16E-02 19.82 (4320,6,109,3) HIR3 ASF1 HPC2 assembly DOT1 BMH1 RAD9 RAD24 MRC1 DDC1 SGS1 GO:0000077 DNA damage checkpoint 2.23E-10 6.00E-08 18.77 (4320,19,109,9) BRE1 RAD17 RAD52 IES5 RAD57 SGS1 BRE1 RAD50 GO:0000722 telomere maintenance via recombination 5.09E-08 4.23E-06 17.34 (4320,16,109,7) NHP10 GO:0000729 DNA double-strand break processing 5.08E-04 1.86E-02 16.99 (4320,7,109,3) RIF1 SGS1 RAD50 GO:0030472 mitotic spindle organization in nucleus 5.08E-04 1.84E-02 16.99 (4320,7,109,3) CIK1 RRD1 RRD2 DNA replication-independent nucleosome GO:0034724 7.98E-04 2.80E-02 14.86 (4320,8,109,3) HIR3 ASF1 HPC2 organization

M. Dubarry et al. 11 SI GO:0044774 mitotic DNA integrity checkpoint 1.47E-06 9.58E-05 14.86 (4320,16,109,6) DOT1 RAD9 MRC1 DDC1 SGS1 BRE1 GO:0008156 negative regulation of DNA replication 1.10E-04 4.91E-03 14.41 (4320,11,109,4) CSM3 RAD9 MRC1 CHD1 CSM3 DOT1 BMH1 RAD9 RAD24 MRC1 GO:0031570 DNA integrity checkpoint 6.20E-10 1.34E-07 14.15 (4320,28,109,10) DDC1 SGS1 BRE1 RAD17 CSM3 RAD9 TEN1 BDF2 SRS2 MRC1 SGS1 GO:0000726 non-recombinational repair 4.53E-05 2.25E-03 11.66 (4320,17,109,5) RAD50 CHD1 GO:0006312 mitotic recombination 1.30E-06 8.66E-05 11.56 (4320,24,109,7) RAD52 SRS2 RSC8 RAD50 XRS2 RAD52 IES5 RAD57 SGS1 BRE1 RAD50 GO:0051053 negative regulation of DNA metabolic process 3.77E-08 3.46E-06 11.51 (4320,31,109,9) NHP10 GO:0031056 regulation of histone modification 3.16E-04 1.23E-02 11.32 (4320,14,109,4) RTF1 HIR3 ASF1 CHD1 ASF1 CHD1 double-strand break repair via nonhomologous GO:0006303 4.22E-04 1.56E-02 10.57 (4320,15,109,4) SRS2 RSC8 RAD50 XRS2 end joining RAD52 IES5 TEN1 MRC1 RAD50 RIF1 RAD57 GO:0000723 telomere maintenance 1.74E-10 5.79E-08 10.10 (4320,51,109,13) SGS1 BRE1 SWD3 NHP10 XRS2 SWD1 RAD52 IES5 TEN1 MRC1 RAD50 RIF1 RAD57 GO:0060249 anatomical structure homeostasis 1.74E-10 5.38E-08 10.10 (4320,51,109,13) SGS1 BRE1 SWD3 NHP10 XRS2 SWD1 RAD52 IES5 TEN1 MRC1 RAD50 RIF1 RAD57 GO:0032200 telomere organization 2.28E-10 5.78E-08 9.91 (4320,52,109,13) SGS1 BRE1 SWD3 NHP10 XRS2 SWD1 DOT1 RAD52 CTF18 CTF4 POL32 DDC1 GO:0000725 recombinational repair 1.05E-07 7.96E-06 8.81 (4320,45,109,10) SGS1 BRE1 RAD50 XRS2 GO:0007064 mitotic sister chromatid cohesion 2.70E-04 1.08E-02 8.26 (4320,24,109,5) CSM3 CTF18 CTF4 MRC1 CTF8 GO:0006289 nucleotide-excision repair 6.65E-05 3.23E-03 8.20 (4320,29,109,6) RTF1 DOT1 RAD9 RAD24 POL32 ELC1 transcription elongation from RNA polymerase GO:0006368 6.65E-05 3.19E-03 8.20 (4320,29,109,6) RTF1 SPT2 HIR3 RSC8 HPC2 CHD1 II promoter double-strand break repair via homologous GO:0000724 2.01E-05 1.11E-03 7.93 (4320,35,109,7) RAD52 CTF18 CTF4 POL32 SGS1 BRE1 recombination RAD50 RAD52 CTF18 CTF4 POL32 SRS2 SGS1 GO:0006302 double-strand break repair 4.76E-08 4.11E-06 7.32 (4320,65,109,12) RSC8 BRE1 RAD50 RAD17 NHP10 XRS2 SPN1 HIR3 ASF1 RSC8 HPC2 NHP10 SWC5 GO:0034728 nucleosome organization 1.06E-05 6.16E-04 7.21 (4320,44,109,8) CHD1 GO:0006354 DNA-templated transcription, elongation 1.43E-04 6.23E-03 7.21 (4320,33,109,6) RTF1 SPT2 HIR3 RSC8 HPC2 CHD1 CSM3 DOT1 BMH1 RAD9 RAD24 MRC1 GO:0000075 cell cycle checkpoint 2.31E-07 1.66E-05 7.15 (4320,61,109,11) DDC1 SGS1 BRE1 PPH21 RAD17 DOT1 BMH1 RAD9 MRC1 DDC1 SGS1 BRE1 GO:0007093 mitotic cell cycle checkpoint 1.49E-05 8.58E-04 6.89 (4320,46,109,8) PPH21 regulation of transcription elongation from RNA GO:0034243 6.83E-04 2.42E-02 6.83 (4320,29,109,5) RTF1 CAF40 SPN1 ASF1 YKE2 polymerase II promoter

M. Dubarry et al. 12 SI regulation of DNA-templated transcription, GO:0032784 9.39E-04 3.21E-02 6.39 (4320,31,109,5) RTF1 CAF40 SPN1 ASF1 YKE2 elongation GO:0006348 chromatin silencing at telomere 3.21E-04 1.24E-02 6.26 (4320,38,109,6) DOT1 ASF1 MRC1 BRE1 SWD3 SWD1 DOT1 UPF3 RAD52 IES5 RAD24 POL32 CTF4 GO:0006310 DNA recombination 4.11E-10 9.32E-08 6.05 (4320,118,109,18) RAD50 RAD17 CTF18 RAD57 NMD2 DDC1 MMS4 SGS1 BRE1 NHP10 XRS2 DOT1 BMH1 RAD9 MRC1 DDC1 SGS1 BRE1 GO:0045930 negative regulation of mitotic cell cycle 4.38E-05 2.20E-03 5.98 (4320,53,109,8) PPH21 CSM3 RTF1 RAD9 TEN1 SRS2 BDF2 MRC1 GO:0051052 regulation of DNA metabolic process 1.16E-06 7.82E-05 5.53 (4320,86,109,12) SGS1 MMS4 BRE1 RAD50 CHD1 RAD52 SPN1 NCB2 HIR3 SRS2 ASF1 RAD57 GO:0071824 protein-DNA complex subunit organization 3.06E-06 1.86E-04 5.06 (4320,94,109,12) RSC8 HPC2 NHP10 SWC5 CHD1 DOT1 BMH1 RAD9 CIK1 CLA4 MRC1 DDC1 GO:0007346 regulation of mitotic cell cycle 4.29E-06 2.57E-04 4.90 (4320,97,109,12) SGS1 SIS2 BRE1 PPH21 SMI1 DOT1 RAD52 RAD24 POL32 CTF4 MRC1 RSC8 RAD50 RAD17 CSM3 RTF1 CTF18 GO:0006281 DNA repair 4.58E-11 1.98E-08 4.83 (4320,197,109,24) RAD9 RRD1 SRS2 BDF2 RAD57 MMS4 SGS1 DDC1 BRE1 ELC1 NHP10 XRS2 DOT1 BMH1 HIR3 NCB2 TEN1 MRC1 RAD50 negative regulation of nucleobase-containing GO:0045934 7.43E-10 1.53E-07 4.43 (4320,206,109,23) CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 BDF2 compound metabolic process SRS2 RIF1 HTZ1 SGS1 SKO1 BRE1 SWD3 SWD1 CHD1 RAD52 CIK1 IES5 CTF4 TEN1 MRC1 CTF8 RAD50 CSM3 CTF18 RIF1 SRS2 RAD57 GO:0051276 chromosome organization 1.12E-08 1.42E-06 4.43 (4320,179,109,20) MMS4 SGS1 BRE1 SWD3 NHP10 XRS2 SWD1 DOT1 BMH1 HIR3 NCB2 TEN1 MRC1 RAD50 negative regulation of nitrogen compound GO:0051172 1.10E-09 2.15E-07 4.34 (4320,210,109,23) CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 SRS2 metabolic process BDF2 RIF1 HTZ1 SGS1 SKO1 BRE1 SWD3 SWD1 CHD1 DOT1 BMH1 RAD24 MRC1 RSC8 RAD50 RAD9 CTF18 SGS1 MMS4 ELC1 RAD52 CTF4 GO:0006974 cellular response to DNA damage stimulus 2.10E-10 6.05E-08 4.31 (4320,230,109,25) POL32 RAD17 RTF1 CSM3 RRD1 SRS2 BDF2 RAD57 DDC1 BRE1 NHP10 XRS2 DOT1 HDA3 ASF1 RIF1 HTZ1 MRC1 BRE1 GO:0016458 gene silencing 2.26E-04 9.18E-03 4.25 (4320,84,109,9) SWD3 SWD1 DOT1 RTF1 HDA3 ASF1 BRE1 SWD3 CHD1 GO:0016570 histone modification 5.26E-04 1.89E-02 4.23 (4320,75,109,8) SWD1 DOT1 RTF1 HDA3 ASF1 BRE1 SWD3 SWD1 GO:0016569 covalent chromatin modification 5.26E-04 1.87E-02 4.23 (4320,75,109,8) CHD1 negative regulation of cellular macromolecule DOT1 PAT1 BMH1 TIF5 NCB2 HIR3 MRC1 GO:2000113 1.84E-08 2.09E-06 4.10 (4320,203,109,21) EAP1 CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 biosynthetic process RIF1 HTZ1 SKO1 BRE1 SWD3 SWD1 CHD1

M. Dubarry et al. 13 SI negative regulation of macromolecule DOT1 PAT1 BMH1 TIF5 NCB2 HIR3 MRC1 GO:0010558 2.01E-08 2.23E-06 4.08 (4320,204,109,21) EAP1 CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 biosynthetic process RIF1 HTZ1 SKO1 BRE1 SWD3 SWD1 CHD1 DOT1 RAD24 MRC1 RSC8 RAD50 CTF18 RAD9 RIF1 NMD2 SGS1 MMS4 SWD3 ELC1 GO:0006259 DNA metabolic process 2.86E-12 2.47E-09 3.98 (4320,319,109,32) SWD1 UPF3 RAD52 IES5 POL32 CTF4 TEN1 CTF8 RAD17 CSM3 RTF1 RRD1 SRS2 BDF2 RAD57 DDC1 BRE1 NHP10 XRS2 PAT1 DOT1 BMH1 HIR3 MRC1 PPH21 RAD50 negative regulation of macromolecule GO:0010605 9.29E-11 3.34E-08 3.98 (4320,279,109,28) SPT2 RAD9 RIF1 ASF1 CLA4 HTZ1 SGS1 metabolic process SKO1 SWD3 CHD1 SWD1 TIF5 NCB2 TEN1 EAP1 CSM3 RTF1 HDA3 SRS2 BDF2 BRE1 DOT1 BMH1 RAD9 MRC1 DDC1 SGS1 BRE1 GO:0045786 negative regulation of cell cycle 8.14E-04 2.83E-02 3.96 (4320,80,109,8) PPH21 DOT1 PAT1 BMH1 TIF5 NCB2 HIR3 MRC1 GO:0010629 negative regulation of gene expression 2.16E-07 1.58E-05 3.90 (4320,193,109,19) EAP1 RTF1 SPT2 HDA3 ASF1 RIF1 CLA4 HTZ1 SKO1 BRE1 SWD3 SWD1 DOT1 ASF1 RIF1 HTZ1 MRC1 BRE1 SWD3 GO:0006342 chromatin silencing 9.60E-04 3.26E-02 3.87 (4320,82,109,8) SWD1 negative regulation of gene expression, GO:0045814 9.60E-04 3.23E-02 3.87 (4320,82,109,8) DOT1 ASF1 RIF1 HTZ1 MRC1 BRE1 SWD3 epigenetic SWD1 DOT1 PAT1 BMH1 TIF5 NCB2 HIR3 MRC1 GO:0009890 negative regulation of biosynthetic process 8.32E-08 6.65E-06 3.77 (4320,221,109,21) EAP1 CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 RIF1 HTZ1 SKO1 BRE1 SWD3 SWD1 CHD1 negative regulation of cellular biosynthetic DOT1 PAT1 BMH1 TIF5 NCB2 HIR3 MRC1 GO:0031327 8.32E-08 6.53E-06 3.77 (4320,221,109,21) EAP1 CSM3 RTF1 SPT2 RAD9 HDA3 ASF1 process RIF1 HTZ1 SKO1 BRE1 SWD3 SWD1 CHD1 DOT1 PAT1 SPN1 HIR3 RSC8 SWC5 SPT2 GO:0006325 chromatin organization 2.14E-06 1.32E-04 3.70 (4320,182,109,17) RTF1 HDA3 ASF1 HTZ1 BRE1 SWD3 HPC2 NHP10 CHD1 SWD1 PAT1 DOT1 BMH1 HIR3 MRC1 SIS2 PPH21 RAD50 SPT2 RAD9 RIF1 ASF1 CLA4 HTZ1 GO:0009892 negative regulation of metabolic process 3.29E-10 7.88E-08 3.65 (4320,315,109,29) SGS1 SKO1 SWD3 CHD1 SWD1 TIF5 NCB2 TEN1 EAP1 CSM3 RTF1 HDA3 SRS2 BDF2 BRE1 PAT1 DOT1 BMH1 HIR3 MRC1 RAD50 PPH21 negative regulation of cellular metabolic GO:0031324 3.50E-09 6.56E-07 3.52 (4320,304,109,27) SPT2 RAD9 RIF1 ASF1 HTZ1 SGS1 SKO1 process SWD3 CHD1 SWD1 TIF5 NCB2 TEN1 EAP1 CSM3 RTF1 HDA3 BDF2 SRS2 BRE1 DOT1 RSC8 SWC5 RTF1 HDA3 ASF1 HTZ1 GO:0016568 chromatin modification 8.32E-05 3.74E-03 3.43 (4320,150,109,13) BRE1 HPC2 SWD3 NHP10 SWD1 CHD1 negative regulation of transcription, DNA- GO:0045892 2.95E-05 1.57E-03 3.36 (4320,177,109,15) DOT1 BMH1 HIR3 NCB2 MRC1 SPT2 RTF1 templated HDA3 ASF1 RIF1 HTZ1 BRE1 SKO1 SWD3

M. Dubarry et al. 14 SI SWD1 DOT1 BMH1 RAD9 CIK1 CLA4 MRC1 DDC1 GO:0010564 regulation of cell cycle process 3.73E-04 1.40E-02 3.35 (4320,130,109,11) SGS1 MMS4 BRE1 PPH21 negative regulation of RNA biosynthetic DOT1 BMH1 HIR3 NCB2 MRC1 SPT2 RTF1 GO:1902679 3.15E-05 1.66E-03 3.34 (4320,178,109,15) HDA3 ASF1 RIF1 HTZ1 BRE1 SKO1 SWD3 process SWD1 negative regulation of nucleic acid-templated DOT1 BMH1 HIR3 NCB2 MRC1 SPT2 RTF1 GO:1903507 3.15E-05 1.64E-03 3.34 (4320,178,109,15) HDA3 ASF1 RIF1 HTZ1 BRE1 SKO1 SWD3 transcription SWD1 DOT1 BMH1 HIR3 NCB2 MRC1 SPT2 RTF1 GO:0051253 negative regulation of RNA metabolic process 3.15E-05 1.62E-03 3.34 (4320,178,109,15) HDA3 ASF1 RIF1 HTZ1 BRE1 SKO1 SWD3 SWD1 SWD3 SWD1 DOT1 BMH1 CIK1 MRC1 SIS2 PPH21 RAD9 GO:0051726 regulation of cell cycle 3.72E-04 1.41E-02 2.96 (4320,174,109,13) CLA4 MMS4 SGS1 DDC1 BRE1 SMI1 PAT1 DOT1 BMH1 HIR3 MRC1 SIS2 PPH21 RAD50 SPT2 RAD9 RIF1 ASF1 CLA4 HTZ1 GO:0048519 negative regulation of biological process 1.37E-08 1.68E-06 2.95 (4320,416,109,31) SGS1 SKO1 SWD3 SWD1 CHD1 TIF5 NCB2 TEN1 EAP1 GPB2 RTF1 CSM3 HDA3 BDF2 SRS2 DDC1 BRE1 PAT1 DOT1 BMH1 HIR3 MRC1 PPH21 RAD50 SPT2 RAD9 RIF1 ASF1 HTZ1 SGS1 SKO1 GO:0048523 negative regulation of cellular process 6.85E-08 5.57E-06 2.90 (4320,396,109,29) SWD3 CHD1 SWD1 TIF5 NCB2 TEN1 EAP1 GPB2 CSM3 RTF1 HDA3 BDF2 SRS2 DDC1 BRE1 DOT1 BMH1 UBA4 RAD24 MRC1 RSC8 RAD50 YKL069W RAD9 CTF18 ASF1 SGS1 GO:0033554 cellular response to stress 2.42E-08 2.61E-06 2.88 (4320,426,109,31) MMS4 SKO1 ELC1 RAD52 NCB2 POL32 CTF4 RAD17 RTF1 CSM3 RRD1 BDF2 SRS2 RAD57 YPD1 DDC1 BRE1 NHP10 XRS2 DOT1 BMH1 UBA4 RAD24 MRC1 RSC8 SIS2 RAD50 YKL069W RAD9 CTF18 ASF1 MMS4 SGS1 SKO1 ELC1 RAD52 NCB2 RRD2 POL32 GO:0006950 response to stress 5.11E-09 8.17E-07 2.79 (4320,497,109,35) CTF4 NST1 RAD17 RTF1 CSM3 RRD1 TCO89 BDF2 SRS2 RAD57 YPD1 DDC1 BRE1 NHP10 XRS2 DOT1 BMH1 RAD52 RAD24 RAD50 RAD17 GO:1903046 meiotic cell cycle process 4.07E-04 1.52E-02 2.79 (4320,199,109,14) GPB2 CSM3 RAD57 SGS1 DDC1 MMS4 BRE1 XRS2 DOT1 BMH1 CIK1 HIR3 RRD2 CTF4 MRC1 GO:1903047 mitotic cell cycle process 8.03E-05 3.69E-03 2.71 (4320,263,109,18) RSC8 CTF8 PPH21 CSM3 CTF18 RAD9 RRD1 SGS1 DDC1 BRE1 HPC2 regulation of nucleobase-containing compound GO:0019219 4.31E-09 7.16E-07 2.64 (4320,571,109,38) DOT1 BMH1 HIR3 MRC1 RSC8 RAD50 YKE2 metabolic process SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1

M. Dubarry et al. 15 SI MMS4 SGS1 SKO1 SWD3 SWD1 CHD1 CAF40 RPB7 SPN1 NCB2 TEN1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 NHP10 SMI1 DOT1 BMH1 UBA4 RAD24 MRC1 RSC8 RAD50 YKL069W RAD9 CTF18 ASF1 SGS1 GO:0051716 cellular response to stimulus 2.41E-07 1.70E-05 2.61 (4320,470,109,31) MMS4 SKO1 ELC1 RAD52 NCB2 POL32 CTF4 RAD17 RTF1 CSM3 RRD1 BDF2 SRS2 RAD57 YPD1 DDC1 BRE1 NHP10 XRS2 DOT1 BMH1 HIR3 MRC1 RSC8 RAD50 YKE2 SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 MMS4 SGS1 SKO1 SWD3 SWD1 CHD1 GO:0010468 regulation of gene expression 4.21E-09 7.57E-07 2.59 (4320,597,109,39) CAF40 RPB7 SPN1 NCB2 TEN1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 NHP10 SMI1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 YKE2 SPT2 SOK2 RAD9 regulation of nitrogen compound metabolic GO:0051171 7.10E-09 1.06E-06 2.59 (4320,581,109,38) ELP6 CLA4 RIF1 ASF1 HTZ1 SKO1 SWD3 process SWD1 CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 EAP1 SWC5 GPB2 RTF1 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 DOT1 BMH1 CIK1 HIR3 TEN1 PPH21 RTF1 GO:0033043 regulation of organelle organization 9.73E-04 3.25E-02 2.56 (4320,217,109,14) ASF1 BDF2 CLA4 SGS1 DDC1 MMS4 CHD1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 YKE2 SPT2 SOK2 RAD9 regulation of cellular macromolecule GO:2000112 7.91E-09 1.14E-06 2.53 (4320,610,109,39) ELP6 RIF1 ASF1 HTZ1 SKO1 SWD3 SWD1 biosynthetic process CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 EAP1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 YKE2 SPT2 SOK2 RAD9 regulation of macromolecule biosynthetic GO:0010556 9.56E-09 1.25E-06 2.52 (4320,614,109,39) ELP6 RIF1 ASF1 HTZ1 SKO1 SWD3 SWD1 process CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 EAP1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 PAT1 RPS0B HIR3 MRC1 RSC8 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 GO:0090304 nucleic acid metabolic process 6.12E-16 2.64E-12 2.47 (4320,1060,109,66) HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 IES5 NCB2 POL32 CTF4 TEN1 EAP1 RAD17 CSM3

M. Dubarry et al. 16 SI RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 YKE2 SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1 SWD3 SWD1 GO:0009889 regulation of biosynthetic process 2.75E-08 2.83E-06 2.43 (4320,637,109,39) CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 EAP1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 YKE2 SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1 SWD3 SWD1 GO:0031326 regulation of cellular biosynthetic process 2.75E-08 2.76E-06 2.43 (4320,637,109,39) CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 EAP1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 DOT1 BMH1 HIR3 MRC1 RSC8 YKE2 SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1 GO:0051252 regulation of RNA metabolic process 7.52E-07 5.15E-05 2.43 (4320,521,109,32) SWD3 CHD1 SWD1 RPB7 CAF40 SPN1 NCB2 SWC5 GPB2 RTF1 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 SUI2 RPS1B RPS0B DOT1 RPS9B BMH1 RPL14A HIR3 RPL31B MRC1 RSC8 SPT2 SOK2 CTF18 ELP6 ASF1 HTZ1 SGS1 SKO1 GO:0034645 cellular macromolecule biosynthetic process 1.37E-08 1.65E-06 2.40 (4320,677,109,41) FRS2 CHD1 RAD52 CAF40 RPB7 RPC11 SPN1 TIF5 NCB2 POL32 CTF4 TEN1 CTF8 SWC5 RTF1 HDA3 RPS20 BDF2 BRE1 HPC2 SMI1 NHP10 DOT1 BMH1 UBA4 RAD24 MRC1 RSC8 SIS2 RAD50 YKL069W RAD9 CTF18 YKL075C CLA4 ASF1 MMS4 SGS1 SKO1 ELC1 RAD52 GO:0050896 response to stimulus 9.57E-08 7.37E-06 2.40 (4320,610,109,37) NCB2 RRD2 POL32 CTF4 NST1 RAD17 RTF1 CSM3 RRD1 TCO89 BDF2 SRS2 RAD57 YPD1 DDC1 BRE1 NHP10 XRS2 DOT1 BMH1 HIR3 MRC1 RSC8 YKE2 SPT2 SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1 GO:2001141 regulation of RNA biosynthetic process 1.64E-06 1.04E-04 2.40 (4320,512,109,31) SWD3 CHD1 SWD1 CAF40 SPN1 NCB2 SWC5 GPB2 RTF1 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 DOT1 BMH1 HIR3 MRC1 RSC8 YKE2 SPT2 regulation of nucleic acid-templated SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1 GO:1903506 1.64E-06 1.02E-04 2.40 (4320,512,109,31) SWD3 CHD1 SWD1 CAF40 SPN1 NCB2 transcription SWC5 GPB2 RTF1 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 DOT1 BMH1 HIR3 MRC1 RSC8 YKE2 SPT2 GO:0006355 regulation of transcription, DNA-templated 1.57E-06 1.01E-04 2.40 (4320,511,109,31) SOK2 RAD9 ELP6 RIF1 ASF1 HTZ1 SKO1

M. Dubarry et al. 17 SI SWD3 CHD1 SWD1 CAF40 SPN1 NCB2 SWC5 GPB2 RTF1 HDA3 RRD1 IMP2' BDF2 BRE1 HPC2 NHP10 SMI1 PAT1 DOT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 PPH21 RAD50 YKE2 SPT2 SOK2 RAD9 ELP6 CLA4 RIF1 ASF1 HTZ1 GO:0009059 macromolecule biosynthetic process 3.00E-08 2.88E-06 2.34 (4320,695,109,41) MMS4 SGS1 SKO1 SWD3 SWD1 CHD1 CAF40 RPB7 SPN1 TIF5 NCB2 TEN1 EAP1 SWC5 GPB2 RTF1 CSM3 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 NHP10 SMI1 SUI2 RPS1B RPS0B DOT1 RPS9B BMH1 RPL14A HIR3 RPL31B MRC1 RSC8 SPT2 SOK2 CTF18 ELP6 ASF1 HTZ1 SGS1 SKO1 GO:0006351 transcription, DNA-templated 7.39E-05 3.46E-03 2.34 (4320,389,109,23) FRS2 CHD1 RAD52 CAF40 RPB7 RPC11 SPN1 TIF5 NCB2 POL32 CTF4 TEN1 CTF8 SWC5 RTF1 HDA3 RPS20 BDF2 BRE1 HPC2 SMI1 NHP10 DOT1 CAF40 RPB7 RPC11 SPN1 HIR3 NCB2 RSC8 SWC5 SPT2 RTF1 SOK2 HDA3 ELP6 GO:0097659 nucleic acid-templated transcription 7.39E-05 3.43E-03 2.34 (4320,389,109,23) BDF2 ASF1 HTZ1 SKO1 BRE1 HPC2 SMI1 NHP10 CHD1 DOT1 CAF40 RPB7 RPC11 SPN1 HIR3 NCB2 RSC8 SWC5 SPT2 RTF1 SOK2 HDA3 ELP6 GO:0060255 regulation of macromolecule metabolic process 4.27E-09 7.37E-07 2.33 (4320,764,109,45) BDF2 ASF1 HTZ1 SKO1 BRE1 HPC2 SMI1 NHP10 CHD1 regulation of transcription from RNA BMH1 CAF40 SPN1 NCB2 HIR3 YKE2 GPB2 GO:0006357 3.71E-04 1.42E-02 2.33 (4320,323,109,19) RTF1 SPT2 HDA3 RAD9 RRD1 IMP2' ELP6 polymerase II promoter ASF1 HTZ1 SKO1 HPC2 CHD1 DOT1 BMH1 CIK1 HIR3 RAD24 MRC1 RSC8 RAD50 PPH21 CTF18 RAD9 SGS1 MMS4 GO:0022402 cell cycle process 3.21E-05 1.63E-03 2.30 (4320,449,109,26) RAD52 RRD2 CTF4 CTF8 RAD17 GPB2 CSM3 RRD1 RAD57 DDC1 BRE1 HPC2 XRS2 DOT1 CAF40 RPB7 RPC11 SPN1 HIR3 NCB2 RSC8 SWC5 SPT2 RTF1 SOK2 HDA3 ELP6 GO:0032774 RNA biosynthetic process 1.38E-04 6.06E-03 2.25 (4320,405,109,23) BDF2 ASF1 HTZ1 SKO1 BRE1 HPC2 SMI1 NHP10 CHD1 DOT1 PAT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 RAD50 PPH21 YKE2 SPT2 SOK2 RAD9 ELP6 ASF1 RIF1 HTZ1 MMS4 GO:0080090 regulation of primary metabolic process 2.80E-08 2.74E-06 2.24 (4320,780,109,44) SGS1 SKO1 SWD3 CHD1 SWD1 RPB7 CAF40 TIF5 SPN1 NCB2 TEN1 EAP1 SWC5 GPB2 CSM3 RTF1 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 SMI1 NHP10

M. Dubarry et al. 18 SI RPS9B RAD52 SPN1 IES5 RPL31B TEN1 GO:0065008 regulation of biological quality 9.91E-04 3.29E-02 2.22 (4320,322,109,18) MRC1 RAD50 TIM50 RIF1 RAD57 SGS1 BRE1 SWD3 NHP10 XRS2 CHD1 SWD1 SWD1 DOT1 PAT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 RAD50 PPH21 YKE2 SPT2 SOK2 RAD9 ELP6 ASF1 RIF1 HTZ1 MMS4 GO:0031323 regulation of cellular metabolic process 5.07E-08 4.29E-06 2.19 (4320,795,109,44) SGS1 SKO1 SWD3 CHD1 SWD1 RPB7 CAF40 TIF5 SPN1 NCB2 TEN1 EAP1 SWC5 GPB2 CSM3 RTF1 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 SMI1 NHP10 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B GO:0043933 macromolecular complex subunit organization 1.81E-05 1.02E-03 2.18 (4320,545,109,30) RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 NCB2 IES5 POL32 CTF4 TEN1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 RPS0B PAT1 DOT1 SUI2 CIK1 HIR3 RSC8 nucleobase-containing compound metabolic GIM4 PPH21 YKE2 SPT2 ASF1 HTZ1 SWD3 GO:0006139 2.17E-13 3.12E-10 2.18 (4320,1217,109,67) CHD1 SWD1 RAD52 SPN1 TIF5 NCB2 RRD2 process SWC5 RTF1 HDA3 RRD1 SRS2 RAD57 BRE1 HPC2 NHP10 DOT1 PAT1 RPS9B BMH1 HIR3 RPL31B MRC1 RSC8 SIS2 RAD50 PPH21 YKE2 SPT2 SOK2 RAD9 ELP6 ASF1 RIF1 CLA4 HTZ1 GO:0019222 regulation of metabolic process 3.42E-08 3.20E-06 2.13 (4320,875,109,47) MMS4 SGS1 SKO1 SWD3 CHD1 SWD1 RPB7 CAF40 TIF5 SPN1 NCB2 RRD2 TEN1 EAP1 SWC5 GPB2 CSM3 RTF1 HDA3 RRD1 IMP2' BDF2 SRS2 BRE1 HPC2 NHP10 SMI1 DOT1 CIK1 MRC1 RSC8 RAD50 TIM50 ATG3 CTF18 RIF1 ASF1 SGS1 SWD3 SWD1 CHD1 GO:1902589 single-organism organelle organization 2.78E-05 1.50E-03 2.13 (4320,557,109,30) RAD52 SPN1 IES5 RRD2 CTF4 TEN1 CTF8 TIM10 RTF1 CSM3 HDA3 RRD1 RAD57 BRE1 NHP10 XRS2 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 GO:0006725 cellular aromatic compound metabolic process 2.89E-12 2.08E-09 2.08 (4320,1279,109,67) SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2

M. Dubarry et al. 19 SI CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 IES5 NCB2 POL32 CTF4 TEN1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B GO:0046483 heterocycle metabolic process 3.53E-12 2.18E-09 2.07 (4320,1284,109,67) RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 NCB2 IES5 POL32 CTF4 TEN1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 DOT1 RPS0B RPS1B PAT1 RPS9B UBA4 TRM11 HIR3 LEA1 RSC8 TPT1 SPT2 SOK2 ELP6 ASF1 HTZ1 NMD2 SKO1 FRS2 CHD1 GO:0016070 RNA metabolic process 5.41E-07 3.76E-05 2.06 (4320,829,109,43) UPF3 RPB7 RPC11 CAF40 SPN1 NCB2 LSM7 NHP2 POL32 LSM6 EAP1 SWC5 RTF1 HDA3 BUD21 RPS20 RTT10 BDF2 PUS7 BRE1 HPC2 SMI1 NHP10 DOT1 HIR3 RSC8 SIS2 SPT2 SOK2 ELP6 nucleobase-containing compound biosynthetic GO:0034654 2.68E-04 1.08E-02 2.02 (4320,509,109,26) ASF1 HTZ1 SKO1 CHD1 RAD52 RPC11 RPB7 process CAF40 SPN1 NCB2 POL32 SWC5 RTF1 HDA3 BDF2 BRE1 HPC2 NHP10 SMI1 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B GO:0034641 cellular nitrogen compound metabolic process 7.55E-12 4.07E-09 2.01 (4320,1338,109,68) RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 NCB2 IES5 POL32 CTF4 TEN1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 SPE1 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 GO:1901360 organic cyclic compound metabolic process 1.97E-11 9.42E-09 2.00 (4320,1328,109,67) HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B RPS9B UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 NCB2 IES5 POL32 CTF4 TEN1 EAP1 RAD17 CSM3

M. Dubarry et al. 20 SI RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 PAT1 HIR3 MRC1 RSC8 SIS2 YKE2 SOK2 RAD9 CLA4 RIF1 ASF1 MMS4 SKO1 CAF40 TIF5 SWC5 RTF1 HDA3 RRD1 IMP2' SOK1 HPC2 SMI1 NHP10 DOT1 RPS9B BMH1 CIK1 GO:0050794 regulation of cellular process 1.43E-08 1.67E-06 1.97 (4320,1104,109,55) UBA4 RPL31B YPT6 RAD50 PPH21 SPT2 ELP6 HTZ1 SGS1 SWD3 TPK3 SWD1 CHD1 RPB7 SPN1 NCB2 TEN1 EAP1 GPB2 CSM3 MF(ALPHA)1 TCO89 SRS2 BDF2 DDC1 YPD1 BRE1 PAT1 DOT1 CIK1 MRC1 RSC8 RAD50 TIM50 ATG3 CTF18 CLA4 RIF1 ASF1 MMS4 SGS1 SWD3 TPK3 SWD1 CHD1 RAD52 SPN1 TIF5 GO:0006996 organelle organization 1.82E-05 1.02E-03 1.95 (4320,752,109,37) IES5 RRD2 CTF4 TEN1 CTF8 TIM10 RTF1 CSM3 HDA3 RRD1 SRS2 RAD57 DDC1 BRE1 NHP10 XRS2 PAT1 RPS0B HIR3 MRC1 RSC8 SIS2 TPT1 SOK2 RAD9 ASF1 RIF1 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS1B GO:0006807 nitrogen compound metabolic process 5.14E-11 2.01E-08 1.90 (4320,1461,109,70) RPS9B BMH1 UBA4 TRM11 RAD24 LEA1 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 ALT1 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 IES5 NCB2 POL32 CTF4 TEN1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 SPE1 PAT1 HIR3 MRC1 RSC8 SIS2 YKE2 SOK2 RAD9 CLA4 RIF1 ASF1 MMS4 SKO1 CAF40 TIF5 SWC5 RTF1 HDA3 RRD1 IMP2' SOK1 HPC2 SMI1 NHP10 DOT1 RPS9B BMH1 UBA4 GO:0050789 regulation of biological process 4.61E-08 4.06E-06 1.89 (4320,1172,109,56) CIK1 RPL31B YPT6 RAD50 PPH21 SPT2 ELP6 HTZ1 SGS1 SWD3 TPK3 SWD1 CHD1 RPB7 SPN1 NCB2 RRD2 TEN1 EAP1 GPB2 CSM3 MF(ALPHA)1 TCO89 SRS2 BDF2 DDC1 YPD1 BRE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 GIM4 RSC8 YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3 GO:0044260 cellular macromolecule metabolic process 1.10E-13 2.38E-10 1.85 (4320,1754,109,82) CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B DOT1 RPS9B BMH1 RPL14A UBA4 TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2

M. Dubarry et al. 21 SI ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 CHD1 SWD1 UPF3 RPC11 RPB7 SPN1 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 DOT1 HIR3 RSC8 SIS2 SPT2 SOK2 ELP6 cellular nitrogen compound biosynthetic GO:0044271 9.15E-04 3.16E-02 1.84 (4320,581,109,27) ASF1 HTZ1 SKO1 CHD1 RAD52 RPC11 RPB7 process CAF40 SPN1 NCB2 POL32 SWC5 RTF1 HDA3 BDF2 BRE1 HPC2 NHP10 SMI1 SPE1 PAT1 HIR3 MRC1 RSC8 SIS2 YKE2 TIM50 SOK2 RAD9 CLA4 ASF1 RIF1 MMS4 SKO1 RAD52 CAF40 TIF5 SWC5 RTF1 HDA3 RRD1 IMP2' SOK1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS9B BMH1 UBA4 CIK1 RPL31B GO:0065007 biological regulation 2.73E-08 2.87E-06 1.82 (4320,1327,109,61) YPT6 RAD50 PPH21 SPT2 ELP6 HTZ1 SGS1 SWD3 TPK3 CHD1 SWD1 RPB7 SPN1 IES5 NCB2 RRD2 TEN1 EAP1 GPB2 CSM3 MF(ALPHA)1 TCO89 SRS2 BDF2 DDC1 YPD1 BRE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 GIM4 RSC8 YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B GO:0043170 macromolecule metabolic process 2.02E-12 2.17E-09 1.77 (4320,1834,109,82) DOT1 RPS9B BMH1 RPL14A UBA4 TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2 ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 CHD1 SWD1 UPF3 RPC11 RPB7 SPN1 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 RAD17 CSM3 RPS20 RTT10 SRS2 BDF2 DDC1 PUS7 BRE1 DOT1 RPS0B RPS1B SUI2 RPS9B BMH1 RPL14A HIR3 RPL31B MRC1 RSC8 SIS2 SPT2 SOK2 CTF18 ELP6 ASF1 HTZ1 SGS1 GO:0044249 cellular biosynthetic process 6.91E-05 3.27E-03 1.70 (4320,1025,109,44) SKO1 FRS2 ALT1 CHD1 RAD52 RPB7 RPC11 CAF40 TIF5 SPN1 NCB2 CTF4 POL32 TEN1 CTF8 SWC5 RTF1 HDA3 RPS20 BDF2 BRE1 HPC2 SMI1 SPE1 NHP10 DOT1 RPS0B RPS1B SUI2 RPS9B BMH1 RPL14A HIR3 RPL31B MRC1 RSC8 SIS2 GO:1901576 organic substance biosynthetic process 1.64E-04 6.74E-03 1.64 (4320,1061,109,44) SPT2 SOK2 CTF18 ELP6 ASF1 HTZ1 SGS1 SKO1 FRS2 ALT1 CHD1 RAD52 RPB7 RPC11 CAF40 TIF5 SPN1 NCB2 CTF4 POL32 TEN1

M. Dubarry et al. 22 SI CTF8 SWC5 RTF1 HDA3 RPS20 BDF2 BRE1 HPC2 SMI1 SPE1 NHP10 DOT1 RPS0B RPS1B SUI2 RPS9B BMH1 RPL14A HIR3 RPL31B MRC1 RSC8 SIS2 SPT2 SOK2 CTF18 ELP6 ASF1 HTZ1 SGS1 GO:0009058 biosynthetic process 2.89E-04 1.14E-02 1.61 (4320,1086,109,44) SKO1 FRS2 ALT1 CHD1 RAD52 RPB7 RPC11 CAF40 TIF5 SPN1 NCB2 CTF4 POL32 TEN1 CTF8 SWC5 RTF1 HDA3 RPS20 BDF2 BRE1 HPC2 SMI1 SPE1 NHP10 PAT1 RPS0B SUI2 HIR3 MRC1 GIM4 RSC8 YKE2 TIM50 REI1 CLA4 ASF1 RIF1 MMS4 RAD52 TIF5 NHP2 CTF8 SWC5 APQ12 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 GO:0071840 cellular component organization or biogenesis 2.05E-05 1.12E-03 1.58 (4320,1427,109,57) NHP10 XRS2 DOT1 RPS9B BMH1 CIK1 RAD50 PPH21 ATG3 SPT2 CTF18 HTZ1 SGS1 SWD3 TPK3 SWD1 CHD1 SPN1 IES5 NCB2 RRD2 CTF4 TEN1 TIM10 CSM3 TCO89 SRS2 DDC1 BRE1 PUS7 SUI2 PAT1 RPS0B HIR3 MRC1 RSC8 GIM4 YKE2 TIM50 CLA4 ASF1 RIF1 MMS4 RAD52 TIF5 CTF8 APQ12 SWC5 RTF1 HDA3 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 BMH1 GO:0016043 cellular component organization 8.31E-05 3.77E-03 1.57 (4320,1309,109,52) CIK1 RAD50 PPH21 ATG3 SPT2 CTF18 HTZ1 SGS1 SWD3 TPK3 SWD1 CHD1 SPN1 NCB2 IES5 RRD2 CTF4 TEN1 TIM10 CSM3 TCO89 SRS2 DDC1 BRE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 SIS2 GIM4 RSC8 YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3 CTF8 APQ12 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B DOT1 RPS9B BMH1 RPL14A UBA4 GO:0044238 primary metabolic process 8.69E-09 1.21E-06 1.48 (4320,2322,109,87) TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2 ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 ALT1 CHD1 SWD1 UPF3 RPC11 RPB7 SPN1 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 RAD17 CSM3 RPS20 RTT10 TCO89 SRS2 BDF2 DDC1 PUS7 BRE1 SPE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 SIS2 GIM4 RSC8 YKE2 TPT1 SOK2 RAD9 ASF1 GO:0044237 cellular metabolic process 9.48E-09 1.28E-06 1.46 (4320,2418,109,89) RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3

M. Dubarry et al. 23 SI CTF8 APQ12 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B DOT1 RPS9B BMH1 RPL14A UBA4 TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2 ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 ALT1 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 IES5 NCB2 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 PET20 RAD17 CSM3 RPS20 RTT10 TCO89 SRS2 IPP1 BDF2 DDC1 PUS7 BRE1 SPE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 SIS2 GIM4 RSC8 YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3 CTF8 APQ12 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B DOT1 RPS9B BMH1 RPL14A UBA4 GO:0071704 organic substance metabolic process 1.28E-07 9.51E-06 1.42 (4320,2424,109,87) TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2 ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 ALT1 CHD1 SWD1 UPF3 RPC11 RPB7 SPN1 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 RAD17 CSM3 RPS20 RTT10 TCO89 SRS2 BDF2 DDC1 PUS7 BRE1 SPE1 SUI2 PAT1 RPS0B HIR3 STI1 MRC1 SIS2 GIM4 RSC8 YKL069W YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4 NMD2 MMS4 SKO1 ELC1 RAD52 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 SHR3 CTF8 APQ12 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 SMI1 NHP10 XRS2 RPS1B DOT1 RPS9B BMH1 RPL14A GO:0008152 metabolic process 4.75E-06 2.81E-04 1.31 (4320,2717,109,90) UBA4 TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 SPT2 ATG3 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 FRS2 ALT1 CHD1 SWD1 UPF3 RPB7 RPC11 SPN1 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 PET20 RAD17 CSM3 RPS20 RTT10 TCO89 SRS2 IPP1 BDF2 DDC1 PUS7 BRE1 SPE1

M. Dubarry et al. 24 SI Cellular components

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value GO:0030870 Mre11 complex 6.31E-04 6.03E-02 39.63 (4320,2,109,2) RAD50 XRS2 GO:0030896 checkpoint clamp complex 6.31E-04 5.43E-02 39.63 (4320,2,109,2) DDC1 RAD17 GO:0022627 cytosolic small ribosomal subunit 3.21E-04 3.46E-02 6.26 (4320,38,109,6) RPS1B PAT1 RPS0B RPS9B TIF5 RPS20 PAT1 RAD24 MRC1 RAD9 CTF18 RIF1 HTZ1 SGS1 SWD3 CHD1 SWD1 IES5 CTF4 POL32 GO:0044427 chromosomal part 2.80E-08 8.02E-06 3.42 (4320,290,109,25) TEN1 CTF8 RAD17 SWC5 RTF1 CSM3 HDA3 RRD1 DDC1 BRE1 NHP10 IES5 POL32 CTF4 TEN1 MRC1 RAD17 GO:0044454 nuclear chromosome part 1.82E-05 3.13E-03 3.16 (4320,213,109,17) SWC5 CSM3 CTF18 HDA3 RRD1 RIF1 HTZ1 DDC1 BRE1 NHP10 CHD1 RPS9B MRC1 LEA1 RSC8 RAD50 CTF18 RIF1 HTZ1 SGS1 SWD3 ELC1 CHD1 SWD1 UPF3 RAD52 RPB7 RPC11 IES5 NCB2 LSM7 GO:0044428 nuclear part 3.94E-05 5.65E-03 1.86 (4320,809,109,38) NHP2 POL32 CTF4 LSM6 TEN1 RAD17 SWC5 APQ12 CSM3 RTF1 HDA3 BUD21 RRD1 RAD57 DDC1 BRE1 NHP10 XRS2 PAT1 RPS0B SUI2 HIR3 MRC1 GIM4 RSC8 SIS2 YKE2 TIM50 REI1 RAD9 RIF1 NMD2 MMS4 ELC1 MTC1 CAF40 TIF5 LSM7 PBY1 NHP2 LSM6 CTF8 SWC5 RTF1 HDA3 BUD21 RRD1 RAD57 HPC2 NHP10 XRS2 RPS1B GO:0032991 macromolecular complex 2.47E-10 2.12E-07 1.84 (4320,1506,109,70) RPS9B RPL14A CIK1 TRM11 RAD24 RPL31B LEA1 RAD50 PPH21 CTF18 ELP6 HTZ1 SGS1 SWD3 FRS2 TPK3 CHD1 SWD1 UPF3 RPB7 RPC11 NCB2 IES5 RRD2 POL32 CTF4 TEN1 VMS1 EAP1 RAD17 TIM10 CSM3 RPS20 TCO89 DDC1 BRE1 PAT1 SUI2 CIK1 TRM11 HIR3 RAD24 MRC1 GIM4 RSC8 SIS2 RAD50 PPH21 YKE2 TIM50 CTF18 ELP6 HTZ1 MMS4 SGS1 SWD3 ELC1 FRS2 TPK3 CHD1 SWD1 RPB7 RPC11 GO:0043234 protein complex 9.88E-06 2.12E-03 1.75 (4320,1084,109,48) CAF40 IES5 NCB2 RRD2 CTF4 POL32 VMS1 EAP1 CTF8 RAD17 SWC5 TIM10 CSM3 RTF1 HDA3 TCO89 RAD57 DDC1 HPC2 NHP10 XRS2 PAT1 HIR3 MRC1 SIS2 RSC8 YKL069W GO:0005634 nucleus 1.13E-08 4.84E-06 1.72 (4320,1588,109,69) YKE2 TPT1 SOK2 RAD9 ASF1 RIF1 CLA4

M. Dubarry et al. 25 SI MMS4 SKO1 ELC1 RAD52 CAF40 LSM7 NHP2 LSM6 CTF8 APQ12 SWC5 RTF1 HDA3 BUD21 RRD1 SOK1 RAD57 HPC2 SMI1 NHP10 XRS2 DOT1 RPS9B BMH1 CIK1 RAD24 LEA1 PPH21 RAD50 SPT2 CTF18 ELP6 HTZ1 SGS1 TPK3 SWD3 SWD1 CHD1 UPF3 RPC11 RPB7 SPN1 IES5 NCB2 POL32 CTF4 TEN1 RAD17 CSM3 SRS2 BDF2 IPP1 YPD1 DDC1 PUS7 BRE1 HIR3 STI1 MRC1 RSC8 SIS2 YKE2 TIM50 RAD9 ASF1 CLA4 MMS4 ELC1 MTC1 CAF40 PBY1 CTF8 APQ12 HDA3 BUD21 SOK1 AIM29 RAD57 NHP10 DOT1 RPS1B RPL14A UBA4 CIK1 YPT6 RAD50 ATG3 HTZ1 SGS1 TPK3 SWD1 RPB7 SPN1 IES5 NCB2 RRD2 CTF4 TEN1 EAP1 PET20 GPB2 SRS2 IPP1 BDF2 BRE1 PUS7 SPE1 RPS0B PAT1 SUI2 GO:0044424 intracellular part 1.13E-04 1.39E-02 1.13 (4320,3670,109,105) MTC4 GIM4 YKL069W TPT1 REI1 SOK2 YKL075C RIF1 NMD2 SKO1 RAD52 TIF5 LSM7 NHP2 LSM6 SHR3 YMD8 SWC5 RTF1 RRD1 IMP2' HPC2 SMI1 XRS2 BMH1 RPS9B TRM11 RAD24 RPL31B LEA1 PPH21 SPT2 CTF18 ELP6 SWD3 FRS2 ALT1 CHD1 UPF3 RPC11 POL32 VMS1 NST1 RAD17 TIM10 CSM3 RPS20 RTT10 TCO89 YPD1 DDC1

M. Dubarry et al. 26 SI Table S4 Gene Ontology (GO) analysis of the genetic interactions identified with Pol δ (cdc2-2) mutation

Gene Ontology analysis was performed using Gorilla (Eden et al. 2009), last update May 2015. The GO term and their description are listed. The p-value, the False Discovery Rate (FDR) q-value and the enrichment (defined as follows: N is the total number of genes, B is the total number of genes associated with a specific GO term, n is the number of genes in the top of the user's input list or in the target set when appropriate, b is the number of genes in the intersection. Enrichment = (b/n) / (B/N)) are shown for each GO term and hits with p-values of less than 0.01 were included. Results are listed beginning with GO categories with the highest enrichment.

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value GO:0000709 meiotic joint molecule formation 2.13E-04 2.14E-02 77.84 (4320,3,37,2) RAD51 RAD52 GO:0044819 mitotic G1/S transition checkpoint 2.13E-04 2.09E-02 77.84 (4320,3,37,2) RAD9 BRE1 GO:0097551 mitochondrial double-strand break repair 2.13E-04 2.04E-02 77.84 (4320,3,37,2) RAD50 XRS2 mitochondrial double-strand break repair via GO:0097552 homologous recombination 2.13E-04 2.00E-02 77.84 (4320,3,37,2) RAD50 XRS2 GO:0031571 mitotic G1 DNA damage checkpoint 2.13E-04 1.95E-02 77.84 (4320,3,37,2) RAD9 BRE1 GO:0030491 heteroduplex formation 1.57E-07 2.94E-05 66.72 (4320,7,37,4) RAD51 RAD55 RAD57 RAD54 GO:0000707 meiotic DNA recombinase assembly 4.24E-04 3.51E-02 58.38 (4320,4,37,2) RAD55 RAD57 negative regulation of cell cycle G1/S phase GO:1902807 transition 4.24E-04 3.45E-02 58.38 (4320,4,37,2) RAD9 BRE1 negative regulation of G1/S transition of mitotic GO:2000134 cell cycle 4.24E-04 3.38E-02 58.38 (4320,4,37,2) RAD9 BRE1 GO:0044783 G1 DNA damage checkpoint 4.24E-04 3.32E-02 58.38 (4320,4,37,2) RAD9 BRE1 GO:0032071 regulation of endodeoxyribonuclease activity 7.02E-04 5.05E-02 46.70 (4320,5,37,2) RAD54 RAD50 GO:0006277 DNA amplification 7.02E-04 4.97E-02 46.70 (4320,5,37,2) RAD52 POL32 GO:0000730 DNA recombinase assembly 3.15E-05 3.57E-03 43.78 (4320,8,37,3) RAD52 RAD55 RAD57 GO:0031573 intra-S DNA damage checkpoint 3.15E-05 3.48E-03 43.78 (4320,8,37,3) RAD9 DDC1 BRE1 GO:0000722 telomere maintenance via recombination 1.95E-09 1.68E-06 43.78 (4320,16,37,6) RAD51 RAD52 RAD57 RAD54 BRE1 RAD50 GO:0000077 DNA damage checkpoint 6.47E-09 3.10E-06 36.87 (4320,19,37,6) BMH1 RAD9 RAD24 DDC1 BRE1 RAD17

M. Dubarry et al. 27 SI GO:0044773 mitotic DNA damage checkpoint 6.66E-05 7.18E-03 35.03 (4320,10,37,3) RAD9 DDC1 BRE1 GO:0042138 meiotic DNA double-strand break formation 6.66E-05 7.01E-03 35.03 (4320,10,37,3) BRE1 RAD50 XRS2 GO:0006312 mitotic recombination 3.11E-08 9.58E-06 29.19 (4320,24,37,6) RAD51 RAD52 RAD57 RAD54 BRE1 RAD50 GO:0006284 base-excision repair 1.56E-04 1.60E-02 26.94 (4320,13,37,3) POL32 RAD50 XRS2 GO:0031570 DNA integrity checkpoint 1.06E-07 2.30E-05 24.16 (4320,29,37,6) BMH1 RAD9 RAD24 DDC1 BRE1 RAD17 GO:0044774 mitotic DNA integrity checkpoint 3.00E-04 2.64E-02 21.89 (4320,16,37,3) RAD9 DDC1 BRE1 GO:0000726 non-recombinational repair 3.62E-04 3.12E-02 20.60 (4320,17,37,3) RAD52 RAD50 XRS2 double-strand break repair via break-induced GO:0000727 replication 5.10E-04 3.93E-02 18.44 (4320,19,37,3) RAD52 POL32 RAD50 RAD51 RAD52 TEN1 RAD57 RAD54 BRE1 GO:0000723 telomere maintenance 6.35E-09 3.91E-06 18.31 (4320,51,37,8) RAD50 XRS2 RAD51 RAD52 TEN1 RAD57 RAD54 BRE1 GO:0060249 anatomical structure homeostasis 6.35E-09 3.42E-06 18.31 (4320,51,37,8) RAD50 XRS2 RAD52 POL32 DDC1 RAD54 BRE1 RAD50 GO:0000725 recombinational repair 6.68E-08 1.52E-05 18.16 (4320,45,37,7) XRS2 RAD51 RAD52 TEN1 RAD57 RAD54 BRE1 GO:0032200 telomere organization 7.46E-09 3.22E-06 17.96 (4320,52,37,8) RAD50 XRS2 double-strand break repair via homologous GO:0000724 recombination 9.39E-06 1.23E-03 16.68 (4320,35,37,5) RAD52 POL32 RAD54 BRE1 RAD50 DNA strand elongation involved in DNA GO:0006271 replication 6.92E-04 5.06E-02 16.68 (4320,21,37,3) POL32 RFC5 PRI1 RAD52 POL32 RAD54 BRE1 RAD50 RAD17 GO:0006302 double-strand break repair 1.01E-06 1.61E-04 12.38 (4320,66,37,7) XRS2 RAD51 RAD52 RAD24 POL32 NMD2 RAD57 GO:0006310 DNA recombination 9.25E-11 1.99E-07 11.98 (4320,117,37,12) DDC1 RAD54 BRE1 RAD50 RAD17 XRS2 GO:0000075 cell cycle checkpoint 1.12E-05 1.42E-03 11.30 (4320,62,37,6) BMH1 RAD9 RAD24 DDC1 BRE1 RAD17 GO:0007093 mitotic cell cycle checkpoint 5.75E-04 4.35E-02 10.15 (4320,46,37,4) BMH1 RAD9 DDC1 BRE1 GO:0045930 negative regulation of mitotic cell cycle 9.89E-04 6.88E-02 8.81 (4320,53,37,4) BMH1 RAD9 DDC1 BRE1 BRE1

GO:0006260 DNA replication 3.90E-04 3.29E-02 7.78 (4320,75,37,5) LGE1 POL32 TEN1 RFC5 PRI1 RAD51 RAD52 RAD55 RAD24 POL32 RAD50 GO:0006281 DNA repair 3.38E-09 2.43E-06 7.70 (4320,197,37,13) RAD17 RAD9 RAD57 RAD54 DDC1 BRE1 XRS2 RAD51 BMH1 RAD52 RAD55 RAD24 POL32 GO:0006974 cellular response to DNA damage stimulus 1.64E-10 2.36E-07 7.61 (4320,230,37,15) RMI1 RAD50 RAD17 RAD9 RAD57 RAD54 DDC1

M. Dubarry et al. 28 SI BRE1 XRS2 RAD51 RAD52 RAD55 RAD24 LGE1 POL32 RMI1 TEN1 RFC5 RAD50 RAD17 RAD9 RAD57 GO:0006259 DNA metabolic process 6.89E-13 2.97E-09 7.09 (4320,313,37,19) NMD2 RAD54 DDC1 BRE1 XRS2 PRI1 RAD51 RAD52 BMH1 LGE1 RAD24 RAD55 GO:1903046 meiotic cell cycle process 4.93E-08 1.42E-05 6.97 (4320,201,37,12) RAD57 DDC1 BRE1 RAD50 RAD17 XRS2 GO:0051052 regulation of DNA metabolic process 6.59E-04 4.90E-02 6.95 (4320,84,37,5) RAD9 TEN1 RAD54 BRE1 RAD50 RAD51 RAD52 RMI1 TEN1 RAD57 RAD54 BRE1 GO:0051276 chromosome organization 1.53E-06 2.35E-04 6.52 (4320,179,37,10) RAD50 RFC5 XRS2 RAD51 RAD52 TEN1 RAD57 PMR1 RAD54 GO:0042592 homeostatic process 2.79E-05 3.25E-03 5.36 (4320,196,37,9) BRE1 RAD50 XRS2 RAD51 RAD52 BMH1 NCB2 RAD55 RAD24 POL32 RMI1 RAD50 RAD17 RAD9 RAD57 GO:0033554 cellular response to stress 1.11E-07 2.28E-05 4.39 (4320,426,37,16) RAD54 DDC1 BRE1 XRS2 RAD51 RAD52 BMH1 NCB2 RAD55 RAD24 POL32 RMI1 RAD50 RAD17 RAD9 RAD57 GO:0051716 cellular response to stimulus 4.40E-07 7.60E-05 3.97 (4320,470,37,16) RAD54 DDC1 BRE1 XRS2 RAD51 RAD52 BMH1 RAD55 LGE1 RAD24 RMI1 RAD50 RFC5 RAD17 RAD9 RAD57 DDC1 BRE1 GO:0022402 cell cycle process 1.67E-06 2.40E-04 3.87 (4320,452,37,15) XRS2 RAD51 RAD52 BMH1 NCB2 RAD55 RAD24 POL32 RMI1 RAD50 RAD17 RAD9 RAD57 GO:0006950 response to stress 9.26E-07 1.54E-04 3.77 (4320,496,37,16) RAD54 DDC1 BRE1 XRS2 RAD51 RAD52 LGE1 TEN1 RAD57 PMR1 GO:0065008 regulation of biological quality 2.60E-04 2.34E-02 3.63 (4320,322,37,10) RAD54 BRE1 RAD50 XRS2 RAD51 RAD52 BMH1 NCB2 RAD55 RAD24 POL32 RMI1 RAD50 RAD17 RAD9 RAD57 GO:0050896 response to stimulus 1.48E-05 1.77E-03 3.06 (4320,610,37,16) RAD54 DDC1 BRE1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 GO:0090304 nucleic acid metabolic process 5.65E-10 6.09E-07 2.99 (4320,1054,37,27) INO2 RAD57 DDC1 BRE1 SMI1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 nucleobase-containing compound metabolic CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 GO:0006139 process 1.57E-08 6.16E-06 2.60 (4320,1211,37,27) INO2 RAD57 DDC1 BRE1 SMI1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 GO:0006725 cellular aromatic compound metabolic process 5.08E-08 1.37E-05 2.48 (4320,1273,37,27) INO2 RAD57 DDC1 BRE1 SMI1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 GO:0046483 heterocycle metabolic process 5.56E-08 1.41E-05 2.47 (4320,1278,37,27) NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1

M. Dubarry et al. 29 SI CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 INO2 RAD57 DDC1 BRE1 SMI1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 GO:0034641 cellular nitrogen compound metabolic process 2.22E-08 7.98E-06 2.45 (4320,1332,37,28) INO2 RAD57 DDC1 BRE1 SPE1 SMI1 XRS2 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 GO:1901360 organic cyclic compound metabolic process 1.24E-07 2.43E-05 2.38 (4320,1323,37,27) INO2 RAD57 DDC1 BRE1 SMI1 XRS2 BMH1 RAD55 LGE1 RAD24 LEA1 RAD50 RAD9 CFD1 NMD2 HTZ1 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 RFC5 RAD17 INO2 RAD57 DDC1 BRE1 SPE1 SMI1 GO:0006807 nitrogen compound metabolic process 2.85E-08 9.46E-06 2.33 (4320,1455,37,29) XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 HTZ1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2 RAD57 DDC1 GO:0044260 cellular macromolecule metabolic process 6.48E-08 1.55E-05 2.08 (4320,1744,37,31) BRE1 SMI1 XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 HTZ1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2 RAD57 DDC1 GO:0043170 macromolecule metabolic process 2.20E-07 3.96E-05 1.98 (4320,1824,37,31) BRE1 SMI1 XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 INP52 HTZ1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2 RAD57 GO:0044238 primary metabolic process 3.68E-06 5.13E-04 1.67 (4320,2314,37,33) DDC1 BRE1 SPE1 SMI1 XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 INP52 HTZ1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2 IPP1 GO:0044237 cellular metabolic process 1.64E-06 2.44E-04 1.65 (4320,2409,37,34) RAD57 DDC1 BRE1 SPE1 SMI1 XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 INP52 HTZ1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2 RAD57 GO:0071704 organic substance metabolic process 1.27E-05 1.57E-03 1.59 (4320,2416,37,33) DDC1 BRE1 SPE1 SMI1 XRS2 BMH1 GPI15 RAD55 LGE1 RAD24 LEA1 RAD50 PRE8 RAD9 CFD1 INP52 HTZ1 PMR1 NMD2 RAD54 PRI1 RAD51 RAD52 SAD1 CAF40 NCB2 GO:0008152 metabolic process 7.66E-06 1.03E-03 1.51 (4320,2709,37,35) POL32 RMI1 TEN1 SHR3 RFC5 RAD17 INO2

M. Dubarry et al. 30 SI IPP1 RAD57 DDC1 BRE1 SPE1 SMI1 XRS2

Cellular components

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value

GO:0030870 Mre11 complex 7.14E-05 2.05E-02 116.76 (4320,2,37,2) RAD50 XRS2 GO:0030896 checkpoint clamp complex 7.14E-05 1.53E-02 116.76 (4320,2,37,2) DDC1 RAD17 GO:0033061 DNA recombinase mediator complex 7.14E-05 1.23E-02 116.76 (4320,2,37,2) RAD55 RAD57 GO:0033062 Rhp55-Rhp57 complex 7.14E-05 1.02E-02 116.76 (4320,2,37,2) RAD55 RAD57 GO:0031389 Rad17 RFC-like complex 7.02E-04 6.71E-02 46.70 (4320,5,37,2) RAD24 RFC5 RAD9 RAD24 POL32 RMI1 TEN1 HTZ1 DDC1 GO:0044427 chromosomal part 1.89E-05 8.12E-03 4.41 (4320,291,37,11) BRE1 RFC5 RAD17 PRI1 RMI1 POL32 TEN1 HTZ1 DDC1 BRE1 RAD17 GO:0044454 nuclear chromosome part 3.65E-04 3.92E-02 4.34 (4320,215,37,8) PRI1 RAD51 SAD1 RAD52 NCB2 RAD55 POL32 RMI1 TEN1 LEA1 RAD50 RAD17 RAD57 HTZ1 DDC1 GO:0044428 nuclear part 1.37E-04 1.69E-02 2.45 (4320,811,37,17) BRE1 PRI1 XRS2 BMH1 LGE1 RAD55 RAD24 LEA1 RAD50 PRE8 RAD9 HTZ1 RAD54 RAD51 RAD52 SAD1 CAF40 NCB2 RMI1 POL32 TEN1 RFC5 RAD17 INO2 IPP1 GO:0005634 nucleus 7.84E-06 6.74E-03 1.98 (4320,1591,37,27) RAD57 DDC1 BRE1 SMI1 XRS2

M. Dubarry et al. 31 SI Table S5 Gene Ontology (GO) analysis of the genetic interactions identified with Pol ε (pol2-12) mutation

From negative genetic interactions:

Cellular processes

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value positive regulation of stress-activated MAPK GO:0032874 6.70E-05 2.89E-03 24.49 (4334,3,177,3) HOS2 SNT1 SIF2 cascade positive regulation of stress-activated protein GO:0070304 6.70E-05 2.87E-03 24.49 (4334,3,177,3) HOS2 SNT1 SIF2 kinase signaling cascade GO:0048478 replication fork protection 6.70E-05 2.84E-03 24.49 (4334,3,177,3) CSM3 CHK1 MRC1 GO:0032872 regulation of stress-activated MAPK cascade 2.60E-04 8.77E-03 18.36 (4334,4,177,3) HOS2 SNT1 SIF2 regulation of stress-activated protein kinase GO:0070302 2.60E-04 8.71E-03 18.36 (4334,4,177,3) HOS2 SNT1 SIF2 signaling cascade GO:0018202 peptidyl-histidine modification 3.78E-05 1.80E-03 16.32 (4334,6,177,4) DPH5 DPH2 DPH6 JJJ3 GO:0017182 peptidyl-diphthamide metabolic process 3.78E-05 1.78E-03 16.32 (4334,6,177,4) DPH5 DPH2 JJJ3 DPH6 peptidyl-diphthamide biosynthetic process from GO:0017183 3.78E-05 1.76E-03 16.32 (4334,6,177,4) DPH5 DPH2 DPH6 JJJ3 peptidyl-histidine GO:0002143 tRNA wobble position uridine thiolation 6.30E-04 1.83E-02 14.69 (4334,5,177,3) TUM1 UBA4 URM1 negative regulation of DNA-dependent DNA GO:2000104 6.30E-04 1.82E-02 14.69 (4334,5,177,3) CSM3 CHK1 MRC1 replication GO:0031573 intra-S DNA damage checkpoint 1.66E-04 6.11E-03 12.24 (4334,8,177,4) RAD9 MRC1 DDC1 BRE1 DNA-dependent DNA replication maintenance GO:0045005 2.29E-05 1.25E-03 12.24 (4334,10,177,5) CSM3 MMS22 DPB2 CHK1 MRC1 of fidelity GO:0044773 mitotic DNA damage checkpoint 2.29E-05 1.24E-03 12.24 (4334,10,177,5) RAD9 MRC1 DDC1 DPB11 BRE1

M. Dubarry et al. 32 SI GO:0043486 histone exchange 4.06E-05 1.87E-03 11.13 (4334,11,177,5) SWR1 ARP6 ASF1 VPS71 SWC5 GO:1902806 regulation of cell cycle G1/S phase transition 2.88E-04 9.51E-03 10.88 (4334,9,177,4) RAD9 BRE1 DCR2 XRN1 GO:2000045 regulation of G1/S transition of mitotic cell cycle 2.88E-04 9.44E-03 10.88 (4334,9,177,4) RAD9 BRE1 DCR2 XRN1 RAD9 RAD24 CHK1 MRC1 DDC1 DPB11 BRE1 GO:0000077 DNA damage checkpoint 3.40E-07 3.06E-05 10.31 (4334,19,177,8) RAD17 GO:0000722 telomere maintenance via recombination 2.43E-05 1.28E-03 9.18 (4334,16,177,6) RAD52 IES5 RAD57 BRE1 RAD50 NHP10 GO:0008156 negative regulation of DNA replication 7.08E-04 2.01E-02 8.90 (4334,11,177,4) CSM3 RAD9 CHK1 MRC1 double-strand break repair via break-induced GO:0000727 7.42E-05 3.11E-03 7.73 (4334,19,177,6) RAD52 PSF1 POL32 DPB11 PSF2 RAD50 replication GO:0016575 histone deacetylation 7.42E-05 3.08E-03 7.73 (4334,19,177,6) HOS2 HDA3 SNT1 SET3 HDA1 SIF2 GO:0044774 mitotic DNA integrity checkpoint 3.25E-04 1.05E-02 7.65 (4334,16,177,5) RAD9 MRC1 DDC1 DPB11 BRE1 CSM3 RAD9 RAD24 CHK1 MRC1 DDC1 DPB11 GO:0031570 DNA integrity checkpoint 1.28E-06 9.18E-05 7.60 (4334,29,177,9) BRE1 RAD17 GO:0006476 protein deacetylation 1.02E-04 4.10E-03 7.35 (4334,20,177,6) HOS2 HDA3 SNT1 SET3 SIF2 HDA1 GO:0098732 macromolecule deacylation 1.39E-04 5.44E-03 7.00 (4334,21,177,6) HOS2 HDA3 SNT1 SET3 SIF2 HDA1 GO:0035601 protein deacylation 1.39E-04 5.39E-03 7.00 (4334,21,177,6) HOS2 HDA3 SNT1 SET3 HDA1 SIF2 GO:0001934 positive regulation of protein phosphorylation 5.96E-04 1.76E-02 6.80 (4334,18,177,5) RTF1 HOS2 SNT1 DPB11 SIF2 GO:0042327 positive regulation of phosphorylation 7.83E-04 2.20E-02 6.44 (4334,19,177,5) RTF1 HOS2 SNT1 DPB11 SIF2 GO:0006312 mitotic recombination 3.10E-04 1.01E-02 6.12 (4334,24,177,6) RAD52 IES5 RAD57 BRE1 RAD50 NHP10 RAD52 PSF1 MMS22 CTF18 POL32 DPB11 DDC1 GO:0000725 recombinational repair 1.17E-06 8.56E-05 5.99 (4334,45,177,11) BRE1 PSF2 RAD50 XRS2 regulation of transcription elongation from RNA GO:0034243 1.22E-04 4.85E-03 5.91 (4334,29,177,7) RTF1 CAF40 SPN1 DST1 ASF1 GIM3 XRN1 polymerase II promoter GO:0045324 late endosome to vacuole transport 3.95E-04 1.24E-02 5.88 (4334,25,177,6) VPS60 VPS30 VPS55 VPS8 VPS13 VPS21 RAD52 IES5 RAD57 MRC1 BRE1 RAD50 BRE2 GO:0000723 telomere maintenance 5.85E-07 4.96E-05 5.76 (4334,51,177,12) SWD3 RRM3 NHP10 SWD1 XRS2 RAD52 IES5 RAD57 MRC1 BRE1 RAD50 BRE2 GO:0060249 anatomical structure homeostasis 5.85E-07 4.86E-05 5.76 (4334,51,177,12) SWD3 RRM3 NHP10 SWD1 XRS2 RAD52 IES5 RAD57 MRC1 BRE1 RAD50 BRE2 GO:0032200 telomere organization 7.34E-07 5.66E-05 5.65 (4334,52,177,12) SWD3 RRM3 NHP10 SWD1 XRS2 double-strand break repair via homologous GO:0000724 6.03E-05 2.66E-03 5.60 (4334,35,177,8) RAD52 PSF1 CTF18 POL32 DPB11 BRE1 PSF2 recombination RAD50

M. Dubarry et al. 33 SI regulation of DNA-templated transcription, GO:0032784 1.93E-04 7.05E-03 5.53 (4334,31,177,7) RTF1 CAF40 SPN1 DST1 ASF1 GIM3 XRN1 elongation GO:0006261 DNA-dependent DNA replication 6.16E-04 1.81E-02 5.44 (4334,27,177,6) PSF1 DPB2 CLB5 LGE1 DPB3 PSF2 positive regulation of transcription elongation GO:0032968 6.16E-04 1.80E-02 5.44 (4334,27,177,6) RTF1 CAF40 DST1 ASF1 GIM3 XRN1 from RNA polymerase II promoter ELP3 SNT1 LGE1 SET3 BRE2 RTF1 HOS2 ARP4 GO:0016570 histone modification 3.17E-08 3.33E-06 5.22 (4334,75,177,16) HDA3 SGF29 ASF1 BRE1 SIF2 HDA1 SWD3 SWD1 ELP3 SNT1 LGE1 SET3 BRE2 RTF1 HOS2 ARP4 GO:0016569 covalent chromatin modification 3.17E-08 3.26E-06 5.22 (4334,75,177,16) HDA3 SGF29 ASF1 BRE1 SIF2 HDA1 SWD3 SWD1 RAD52 POL32 PSF2 RAD50 RAD17 MMS22 PSF1 GO:0006302 double-strand break repair 2.59E-07 2.43E-05 5.19 (4334,66,177,14) CTF18 SRS2 DPB11 BRE1 NHP10 NUP133 XRS2 RAD24 LTE1 BUB2 MRC1 PPH21 RAD17 CSM3 GO:0000075 cell cycle checkpoint 8.16E-07 6.18E-05 5.13 (4334,62,177,13) RAD9 BFA1 CHK1 DPB11 DDC1 BRE1 GO:0006289 nucleotide-excision repair 9.24E-04 2.53E-02 5.07 (4334,29,177,6) RTF1 RAD9 RAD24 POL32 DPB11 SAC3 positive regulation of DNA-templated GO:0032786 9.24E-04 2.51E-02 5.07 (4334,29,177,6) RTF1 CAF40 DST1 ASF1 GIM3 XRN1 transcription, elongation SWR1 SPN1 ARP6 VPS71 ASF1 HIR2 HPC2 GO:0034728 nucleosome organization 6.41E-05 2.80E-03 4.90 (4334,45,177,9) NHP10 SWC5 BFA1 RAD9 LTE1 BUB2 MRC1 DPB11 DDC1 GO:0007093 mitotic cell cycle checkpoint 7.69E-05 3.16E-03 4.79 (4334,46,177,9) BRE1 PPH21 ARP4 SWR1 MRN1 ELF1 ARP6 UME6 VPS71 GO:0006338 chromatin remodeling 1.38E-05 8.30E-04 4.73 (4334,57,177,11) ASF1 HTZ1 NHP10 SWC5 LGE1 HIR2 SWR1 ELF1 ASF1 HTZ1 SWD3 SIF2 SWD1 ELP3 SNT1 RXT3 ARP6 UME6 SET3 GO:0016568 chromatin modification 5.94E-12 1.28E-08 4.51 (4334,152,177,28) VPS71 BRE2 SWC5 RTF1 HOS2 HDA3 ARP4 MRN1 SGF29 BRE1 HDA1 HPC2 NHP10 CSM3 RAD9 CLB5 DIA2 CHK1 MRC1 BRE1 GO:0006275 regulation of DNA replication 3.32E-04 1.06E-02 4.45 (4334,44,177,8) RRM3 GO:0006348 chromatin silencing at telomere 8.54E-04 2.36E-02 4.39 (4334,39,177,7) DIA2 ASF1 MRC1 BRE1 BRE2 SWD3 SWD1 PAT1 LGE1 HIR2 SWR1 ELF1 ASF1 HTZ1 DPB3 SWD3 SIF2 SWD1 ELP3 SNT1 SPN1 RXT3 ARP6 GO:0006325 chromatin organization 7.80E-13 3.37E-09 4.26 (4334,184,177,32) UME6 SET3 VPS71 BRE2 SWC5 RTF1 HOS2 HDA3 ARP4 MRN1 SGF29 DPB2 BRE1 HPC2 HDA1 NHP10 RTF1 HOS2 SNT1 CLB5 CLB2 GPB1 DPB11 LSP1 GO:0042325 regulation of phosphorylation 4.34E-05 1.95E-03 4.21 (4334,64,177,11) CKB2 SIF2 CKB1 HOS2 BFA1 SNT1 RAD9 SET3 BUB2 LTE1 DDC1 GO:0010948 negative regulation of cell cycle process 1.99E-05 1.11E-03 4.20 (4334,70,177,12) DPB11 BRE1 PPH21 SIF2

M. Dubarry et al. 34 SI LGE1 POL32 MRC1 CTF8 PSF2 RRM3 PSF1 GO:0006260 DNA replication 9.08E-06 5.77E-04 4.19 (4334,76,177,13) CTF18 DPB2 CLB5 DCC1 DPB3 DPB11 BFA1 RAD9 BUB2 LTE1 MRC1 DPB11 DDC1 GO:0045930 negative regulation of mitotic cell cycle 2.42E-04 8.42E-03 4.16 (4334,53,177,9) BRE1 PPH21 RTF1 HOS2 SNT1 CLB5 CLB2 DPB11 LSP1 CKB2 GO:0001932 regulation of protein phosphorylation 1.48E-04 5.64E-03 4.01 (4334,61,177,10) SIF2 CKB1 VPS30 VPS60 VPS5 VPS55 VPS29 SNX3 VPS17 GO:0016197 endosomal transport 1.48E-04 5.59E-03 4.01 (4334,61,177,10) VPS8 VPS13 VPS21 SNT1 SET3 LTE1 BUB2 MRC1 PPH21 HOS2 GO:0045786 negative regulation of cell cycle 1.62E-05 9.35E-04 3.98 (4334,80,177,13) RAD9 BFA1 DPB11 DDC1 BRE1 SIF2 VPS60 SOK2 NPR3 UBA4 DFG16 UME6 DIA2 GO:0030447 filamentous growth 1.02E-04 4.12E-03 3.85 (4334,70,177,11) GPB1 RIM8 RIM21 URM1 growth of unicellular organism as a thread of GO:0070783 2.23E-04 7.95E-03 3.83 (4334,64,177,10) SOK2 NPR3 UBA4 DFG16 UME6 DIA2 GPB1 attached cells RIM8 RIM21 URM1 filamentous growth of a population of unicellular GO:0044182 2.23E-04 7.89E-03 3.83 (4334,64,177,10) SOK2 NPR3 UBA4 DFG16 UME6 DIA2 GPB1 organisms RIM8 RIM21 URM1 HOS2 BFA1 SNT1 SET3 BUB2 LTE1 DDC1 GO:0051784 negative regulation of nuclear division 4.87E-04 1.49E-02 3.80 (4334,58,177,9) PPH21 SIF2 HOS2 BFA1 SNT1 SET3 BUB2 LTE1 DDC1 SIF2 GO:0051782 negative regulation of cell division 5.54E-04 1.65E-02 3.74 (4334,59,177,9) PPH21 RAD52 SPN1 NCB2 ARP6 VPS71 HIR2 SWC5 GO:0071824 protein-DNA complex subunit organization 2.41E-05 1.29E-03 3.61 (4334,95,177,14) SRB2 SWR1 SRS2 ASF1 RAD57 HPC2 NHP10 LTE1 BUB2 MRC1 PPH21 DCR2 XRN1 RAD9 GO:0007346 regulation of mitotic cell cycle 3.07E-05 1.56E-03 3.53 (4334,97,177,14) BFA1 CLB5 CLB2 DDC1 DPB11 BRE1 SMI1 RAD52 IES5 RAD24 POL32 PSF2 RAD50 RAD17 GO:0006310 DNA recombination 4.29E-06 2.77E-04 3.53 (4334,118,177,17) CTF18 PSF1 MMS22 RAD57 DDC1 DPB11 BRE1 SOH1 NHP10 XRS2 BFA1 RAD9 BUB2 LTE1 DPB11 BRE1 DCR2 GO:1901990 regulation of mitotic cell cycle phase transition 9.07E-04 2.50E-02 3.50 (4334,63,177,9) PPH21 XRN1 HDA3 DIA2 ASF1 HTZ1 MRC1 BRE1 BRE2 SWD3 GO:0016458 gene silencing 1.44E-04 5.54E-03 3.46 (4334,85,177,12) HDA1 SIR1 SWD1 NUP133 SNT1 UME6 SET3 LTE1 BUB2 MRC1 DCR2 GO:0010564 regulation of cell cycle process 3.96E-06 2.59E-04 3.39 (4334,130,177,18) PPH21 XRN1 HOS2 BFA1 RAD9 CLB5 CLB2 DDC1 DPB11 BRE1 SIF2 LGE1 LTE1 MRC1 TIM50 SHE4 ASF1 SIF2 ELP3 RAD52 VAM10 TRS85 CTF8 RTF1 SWF1 HDA3 MMS22 SGF29 DCC1 SHE1 RAD57 HDA1 BRE1 GO:0006281 DNA repair 1.84E-08 2.04E-06 3.32 (4334,199,177,27) NHP10 SOH1 NUP133 XRS2 VPS30 BUB2 SLT2 SAC3 RAD50 RRM3 CTF18 ATG21 SSO2 SWD3 SWD1 SNT1 SPN1 IES5 ARC18 RRD2 SET3 BRE2 CSM3 HOS2 ARP4 BFA1 CLB2 VAC8 VPS60 SOK2 NPR3 UBA4 DFG16 UME6 DIA2 GO:0040007 growth 2.25E-04 7.89E-03 3.30 (4334,89,177,12) GPB1 RIM8 RIM21 PPH21 URM1

M. Dubarry et al. 35 SI RAD24 MRC1 CKB2 SAC3 RAD50 RRM3 CKB1 CTF18 RAD9 CHK1 DPB3 RAD52 POL32 PSF2 GO:0006974 cellular response to DNA damage stimulus 2.03E-09 3.25E-07 3.27 (4334,232,177,31) RAD17 CSM3 RTF1 ARP4 PSF1 MMS22 DPB2 DCC1 SRS2 RAD57 DPB11 DDC1 BRE1 SOH1 NHP10 XRS2 NUP133 ELP3 UBA4 RRD2 DPH2 PKP1 BRE2 DPH6 ARP4 GO:0018193 peptidyl-amino acid modification 8.41E-05 3.43E-03 3.23 (4334,106,177,14) DPH5 SGF29 ASF1 SWD3 SWD1 JJJ3 CSM3 RTF1 RAD9 CLB5 DIA2 CHK1 SRS2 MRC1 GO:0051052 regulation of DNA metabolic process 5.32E-04 1.60E-02 3.21 (4334,84,177,11) BRE1 RAD50 RRM3 RAD52 IES5 MRC1 CTF8 SAC3 RAD50 RRM3 SIR1 BRE2 CSM3 CTF18 MMS22 ARP4 DCC1 GO:0051276 chromosome organization 6.39E-07 5.11E-05 3.15 (4334,179,177,23) SRS2 RAD57 BRE1 SWD3 SOH1 NHP10 XRS2 NUP133 SWD1 MRC1 SIR1 BRE2 ELF1 DIA2 ASF1 HTZ1 BRE1 GO:0040029 regulation of gene expression, epigenetic 1.98E-04 7.19E-03 3.15 (4334,101,177,13) SIF2 HDA1 SWD3 NUP133 SWD1 PAT1 RIM101 MRC1 HIR2 YGR122W RAD9 CHK1 negative regulation of cellular macromolecule GO:2000113 5.47E-07 4.72E-05 2.99 (4334,205,177,25) ASF1 HTZ1 SWD3 SWD1 TIF5 RXT3 NCB2 UME6 biosynthetic process SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 BRE1 HDA1 NUP133 PAT1 RIM101 MRC1 HIR2 YGR122W RAD9 CHK1 negative regulation of macromolecule GO:0010558 6.00E-07 4.89E-05 2.97 (4334,206,177,25) ASF1 HTZ1 SWD3 SWD1 TIF5 RXT3 NCB2 UME6 biosynthetic process SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 BRE1 HDA1 NUP133 RIM101 MRC1 HIR2 RAD50 YGR122W RAD9 negative regulation of nucleobase-containing GO:0045934 6.59E-07 5.18E-05 2.96 (4334,207,177,25) CHK1 ASF1 HTZ1 SWD3 SWD1 RXT3 NCB2 compound metabolic process UME6 SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 SRS2 BRE1 HDA1 NUP133 RIM101 MRC1 HIR2 RAD50 YGR122W RAD9 negative regulation of nitrogen compound GO:0051172 9.51E-07 7.08E-05 2.90 (4334,211,177,25) CHK1 ASF1 HTZ1 SWD3 SWD1 RXT3 NCB2 metabolic process UME6 SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 SRS2 BRE1 HDA1 NUP133 PAT1 RIM101 BUB2 LTE1 MRC1 PPH21 HIR2 negative regulation of macromolecule RAD50 YGR122W RAD9 CHK1 ASF1 HTZ1 SWD3 GO:0010605 1.48E-08 1.68E-06 2.89 (4334,280,177,33) SWD1 TIF5 RXT3 NCB2 UME6 BRE2 SIR1 CSM3 metabolic process RTF1 SRB2 BFA1 HDA3 CLB2 DIA2 SRS2 LSP1 BRE1 HDA1 NUP133 RAD24 LGE1 MRC1 SAC3 RAD50 RRM3 SHE4 CTF18 RAD9 CHK1 DPB3 SWD3 SWD1 RAD52 IES5 POL32 CTF8 PSF2 RAD17 BRE2 CSM3 GO:0006259 DNA metabolic process 1.80E-09 2.99E-07 2.88 (4334,315,177,37) RTF1 ARP4 PSF1 MMS22 CLB5 DPB2 DCC1 SRS2 RAD57 DPB11 DDC1 BRE1 SOH1 NHP10 XRS2 NUP133 CDC33 SNT1 UME6 SET3 LTE1 BUB2 MRC1 GO:0051726 regulation of cell cycle 2.03E-05 1.12E-03 2.81 (4334,174,177,20) DCR2 PPH21 XRN1 HOS2 BFA1 RAD9 CLB5

M. Dubarry et al. 36 SI CLB2 DDC1 DPB11 BRE1 SIF2 SMI1 PAT1 RIM101 BUB2 LTE1 MRC1 PPH21 HIR2 RAD50 YGR122W RAD9 CHK1 ASF1 HTZ1 SWD3 GO:0009892 negative regulation of metabolic process 7.26E-09 9.22E-07 2.79 (4334,316,177,36) VHS3 SWD1 TIF5 RXT3 NCB2 UME6 GPB1 BRE2 SIR1 CSM3 RTF1 SRB2 BFA1 HDA3 CLB2 DIA2 SRS2 SHE1 LSP1 BRE1 HDA1 NUP133 PAT1 TIF5 RXT3 NCB2 RIM101 UME6 MRC1 HIR2 BRE2 SIR1 YGR122W RTF1 SRB2 HDA3 GO:0010629 negative regulation of gene expression 1.02E-05 6.41E-04 2.76 (4334,195,177,22) DIA2 ASF1 HTZ1 BRE1 SWD3 HDA1 SWD1 NUP133 PAT1 RIM101 MRC1 HIR2 YGR122W RAD9 CHK1 ASF1 HTZ1 SWD3 SWD1 TIF5 RXT3 NCB2 UME6 GO:0009890 negative regulation of biosynthetic process 2.69E-06 1.84E-04 2.75 (4334,223,177,25) SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 BRE1 HDA1 NUP133 PAT1 RIM101 MRC1 HIR2 YGR122W RAD9 CHK1 negative regulation of cellular biosynthetic GO:0031327 2.69E-06 1.81E-04 2.75 (4334,223,177,25) ASF1 HTZ1 SWD3 SWD1 TIF5 RXT3 NCB2 UME6 process SIR1 BRE2 RTF1 CSM3 SRB2 HDA3 DIA2 BRE1 HDA1 NUP133 negative regulation of transcription, DNA- NCB2 RXT3 RIM101 UME6 MRC1 HIR2 BRE2 GO:0045892 3.08E-05 1.55E-03 2.74 (4334,179,177,20) SIR1 RTF1 YGR122W SRB2 HDA3 DIA2 ASF1 templated HTZ1 BRE1 SWD3 HDA1 NUP133 SWD1 PAT1 RIM101 BUB2 LTE1 MRC1 PPH21 HIR2 negative regulation of cellular metabolic RAD50 YGR122W RAD9 CHK1 ASF1 HTZ1 SWD3 GO:0031324 3.60E-08 3.62E-06 2.73 (4334,305,177,34) SWD1 TIF5 NCB2 RXT3 UME6 GPB1 BRE2 SIR1 process CSM3 RTF1 SRB2 BFA1 HDA3 CLB2 DIA2 SRS2 LSP1 BRE1 HDA1 NUP133 negative regulation of RNA biosynthetic NCB2 RXT3 RIM101 UME6 MRC1 HIR2 BRE2 GO:1902679 3.35E-05 1.66E-03 2.72 (4334,180,177,20) SIR1 RTF1 YGR122W SRB2 HDA3 DIA2 ASF1 process HTZ1 BRE1 SWD3 HDA1 NUP133 SWD1 negative regulation of nucleic acid-templated NCB2 RXT3 RIM101 UME6 MRC1 HIR2 BRE2 GO:1903507 3.35E-05 1.64E-03 2.72 (4334,180,177,20) SIR1 RTF1 YGR122W SRB2 HDA3 DIA2 ASF1 transcription HTZ1 BRE1 SWD3 HDA1 NUP133 SWD1 NCB2 RXT3 RIM101 UME6 MRC1 HIR2 BRE2 GO:0051253 negative regulation of RNA metabolic process 3.35E-05 1.62E-03 2.72 (4334,180,177,20) SIR1 RTF1 YGR122W SRB2 HDA3 DIA2 ASF1 HTZ1 BRE1 SWD3 HDA1 NUP133 SWD1 PAT1 NPR3 RIM101 LTE1 BUB2 MRC1 PPH21 RAD50 HIR2 YGR122W EPS1 RAD9 CHK1 ASF1 HTZ1 SWD3 SIF2 VHS3 SWD1 SNT1 TIF5 NCB2 GO:0048519 negative regulation of biological process 1.33E-09 2.30E-07 2.58 (4334,418,177,44) RXT3 UME6 SET3 GPB1 SIR1 BRE2 CSM3 RTF1 SRB2 HOS2 BFA1 HDA3 CLB2 DIA2 SHE1 SRS2 DDC1 DPB11 LSP1 BRE1 HDA1 NUP133 NPR3 VPS30 UBA4 TRR2 RAD24 RIM101 MRC1 GO:0033554 cellular response to stress 9.17E-10 1.80E-07 2.57 (4334,429,177,45) SLT2 NUP188 CKB2 SAC3 RAD50 RRM3 URM1

M. Dubarry et al. 37 SI CKB1 CTF18 RAD9 CHK1 ATG21 ASF1 DPB3 RAD52 NCB2 TRS85 POL32 PSF2 DCR2 RAD17 CSM3 RTF1 MMS22 ARP4 PSF1 DPB2 DCC1 VAC8 SRS2 RAD57 DDC1 DPB11 BRE1 SOH1 NHP10 XRS2 NUP133 PAT1 NPR3 RIM101 LTE1 BUB2 MRC1 PPH21 RAD50 HIR2 YGR122W RAD9 CHK1 ASF1 HTZ1 SWD3 SIF2 SWD1 SNT1 TIF5 NCB2 RXT3 UME6 GO:0048523 negative regulation of cellular process 1.09E-08 1.27E-06 2.52 (4334,398,177,41) SET3 GPB1 SIR1 BRE2 CSM3 RTF1 SRB2 HOS2 BFA1 HDA3 CLB2 DIA2 SRS2 DDC1 DPB11 LSP1 BRE1 HDA1 NUP133 NPR3 VPS30 UBA4 TRR2 RAD24 RIM101 MRC1 SLT2 NUP188 CKB2 SAC3 RAD50 RRM3 URM1 CKB1 CTF18 RAD9 CHK1 ATG21 ASF1 DPB3 GO:0051716 cellular response to stimulus 6.69E-10 1.38E-07 2.48 (4334,473,177,48) RIM21 RAD52 NCB2 TRS85 POL32 PSF2 AZF1 DCR2 RAD17 CSM3 RTF1 SRB2 MMS22 ARP4 PSF1 DPB2 DCC1 VAC8 SRS2 RAD57 DDC1 DPB11 BRE1 SOH1 NHP10 XRS2 NUP133 NPR3 RIM101 MRC1 CKB2 NUP188 CKB1 URM1 RAD9 CHK1 ASF1 DPB3 RAD52 TRS85 RTF1 PSF1 MMS22 DPB2 DCC1 RAD57 NHP10 SOH1 NUP133 XRS2 VPS30 UBA4 TRR2 RAD24 SLT2 GO:0006950 response to stress 4.41E-10 9.52E-08 2.45 (4334,500,177,50) SAC3 RAD50 RRM3 CTF18 ATG21 GET3 NCB2 RRD2 POL32 NST1 PSF2 DCR2 RAD17 CSM3 ARP4 TCO89 VAC8 SRS2 DPB11 DDC1 BRE1 LSP1 RAD52 RIM9 RIM101 RAD24 LGE1 CHS5 RAD50 GO:1903046 meiotic cell cycle process 1.61E-04 6.05E-03 2.44 (4334,201,177,20) RAD17 CSM3 SWF1 MMS22 CLB5 RAD57 DDC1 BRE1 RIM21 VPS13 SSO2 SOH1 XRS2 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 regulation of cellular macromolecule GO:2000112 2.95E-11 2.13E-08 2.36 (4334,613,177,59) SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 biosynthetic process HDA1 SOH1 NHP10 SMI1 NUP133 SAC3 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 MRN1 CLB5 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 regulation of nucleobase-containing compound SIF2 ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 GO:0019219 2.23E-10 5.67E-08 2.35 (4334,574,177,55) SRB2 HDA3 SGF29 DIA2 HPC2 HDA1 SOH1 metabolic process NHP10 SMI1 NUP133 SAC3 RAD50 RRM3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2

M. Dubarry et al. 38 SI ARP4 CLB5 SRS2 BRE1 PAT1 CDC33 HCR1 SNT1 TIF5 BUB2 LTE1 CKB2 GO:0032268 regulation of cellular protein metabolic process 2.57E-04 8.73E-03 2.35 (4334,208,177,20) PPH21 CKB1 RTF1 HOS2 BFA1 MRN1 CLB5 CLB2 ASF1 DPB11 LSP1 SIF2 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 regulation of macromolecule biosynthetic GO:0010556 3.90E-11 1.87E-08 2.34 (4334,617,177,59) SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 process HDA1 NHP10 SOH1 SMI1 NUP133 SAC3 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 MRN1 CLB5 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 ASF1 SIF2 ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 GO:2001141 regulation of RNA biosynthetic process 4.28E-09 5.78E-07 2.33 (4334,516,177,49) HDA3 SGF29 DIA2 HDA1 HPC2 SOH1 NHP10 SMI1 NUP133 SAC3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 HOS2 ARP4 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 ASF1 SIF2 regulation of nucleic acid-templated ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 GO:1903506 4.28E-09 5.61E-07 2.33 (4334,516,177,49) HDA3 SGF29 DIA2 HDA1 HPC2 SOH1 NHP10 transcription SMI1 NUP133 SAC3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 HOS2 ARP4 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 ASF1 SIF2 ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 GO:0006355 regulation of transcription, DNA-templated 4.01E-09 5.59E-07 2.33 (4334,515,177,49) HDA3 SGF29 DIA2 HDA1 HPC2 NHP10 SOH1 SMI1 NUP133 SAC3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 HOS2 ARP4 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 regulation of nitrogen compound metabolic GO:0051171 4.39E-10 9.99E-08 2.31 (4334,584,177,55) SRB2 HDA3 SGF29 DIA2 HPC2 HDA1 NHP10 process SOH1 SMI1 NUP133 SAC3 RAD50 RRM3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 CLB5 SRS2 BRE1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 GO:0051252 regulation of RNA metabolic process 7.74E-09 9.29E-07 2.29 (4334,525,177,49) CKB1 YGR122W SOK2 RAD9 SWR1 ASF1 SIF2

M. Dubarry et al. 39 SI ELP3 CAF40 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HDA1 HPC2 SOH1 NHP10 SMI1 NUP133 SAC3 ELF1 HTZ1 SWD3 SWD1 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 HOS2 ARP4 BRE1 PAT1 HCR1 TRS20 LGE1 SIW14 GIM4 NUP188 HIR2 SWR1 ASF1 DPB3 SIF2 PRE9 ELP3 RAD52 TIF5 ARP6 VPS71 GIM3 SWC5 RTF1 SRB2 HDA3 GO:0043933 macromolecular complex subunit organization 3.75E-09 5.40E-07 2.28 (4334,548,177,51) SGF29 DPB2 RAD57 HDA1 HPC2 NHP10 PPH21 ELF1 HTZ1 BUD27 SWD3 SWD1 SAD1 SNT1 SPN1 RXT3 NCB2 ARC18 RRD2 UME6 SET3 BRE2 HOS2 GCS1 ARP4 MRN1 SRS2 BRE1 PAT1 CDC33 HCR1 SNT1 TIF5 BUB2 LTE1 CKB2 GO:0051246 regulation of protein metabolic process 3.99E-04 1.25E-02 2.28 (4334,215,177,20) PPH21 CKB1 RTF1 HOS2 BFA1 MRN1 CLB5 CLB2 ASF1 DPB11 LSP1 SIF2 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 GO:0009889 regulation of biosynthetic process 1.82E-10 5.24E-08 2.26 (4334,640,177,59) HDA1 NHP10 SOH1 SMI1 NUP133 SAC3 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 MRN1 CLB5 BRE1 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 GO:0031326 regulation of cellular biosynthetic process 1.82E-10 4.92E-08 2.26 (4334,640,177,59) HDA1 SOH1 NHP10 SMI1 NUP133 SAC3 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 MRN1 CLB5 BRE1 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 GO:0010468 regulation of gene expression 1.25E-09 2.25E-07 2.24 (4334,600,177,55) HDA1 SOH1 NHP10 SMI1 NUP133 SAC3 PPH21 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 HOS2 ARP4 MRN1 BRE1 PAT1 NPR3 RIM101 RAD24 LTE1 BUB2 RAD50 CTF18 RAD9 CHK1 VHS3 TRS85 SAP190 SET3 GO:0007049 cell cycle 4.28E-05 1.95E-03 2.21 (4334,310,177,28) CTF8 DCR2 CSM3 BFA1 PSF1 MMS22 CLB5 DPB2 CLB2 DIA2 SHE1 RAD57 DPB11 XRS2

M. Dubarry et al. 40 SI NPR3 RIM101 MRC1 CKB2 NUP188 CKB1 URM1 RAD9 CHK1 ASF1 DPB3 RIM21 RAD52 TRS85 RTF1 SRB2 PSF1 MMS22 DPB2 DCC1 RAD57 SOH1 NHP10 NUP133 XRS2 VPS30 UBA4 TRR2 GO:0050896 response to stimulus 3.00E-09 4.47E-07 2.19 (4334,614,177,55) RAD24 SLT2 SAC3 RAD50 RRM3 CTF18 ATG21 GET3 NCB2 BPH1 RRD2 POL32 NST1 PSF2 AZF1 DCR2 RAD17 CSM3 ARP4 TCO89 VAC8 SRS2 ETP1 DPB11 DDC1 BRE1 LSP1 LGE1 LTE1 MRC1 TIM50 SHE4 ASF1 SIF2 ELP3 RAD52 VAM10 TRS85 CTF8 RTF1 SWF1 HDA3 MMS22 SGF29 DCC1 SHE1 RAD57 HDA1 NHP10 GO:1902589 single-organism organelle organization 2.35E-08 2.54E-06 2.19 (4334,560,177,50) SOH1 NUP133 XRS2 VPS30 BUB2 SLT2 SAC3 RAD50 RRM3 CTF18 ATG21 SSO2 SWD3 SWD1 SNT1 SPN1 IES5 ARC18 RRD2 SET3 BRE2 CSM3 HOS2 ARP4 BFA1 CLB2 VAC8 BRE1 PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 HDA1 SMI1 NHP10 SOH1 NUP133 BUB2 GO:0060255 regulation of macromolecule metabolic process 6.10E-11 2.03E-08 2.14 (4334,766,177,67) SAC3 PPH21 RAD50 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 RXT3 NCB2 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 BFA1 ARP4 MRN1 CLB5 CLB2 SRS2 DPB11 BRE1 LSP1 RRD2 RIM101 SAP190 CHS5 BUB2 LTE1 MRC1 SLT2 SAC3 CTF8 PPH21 CSM3 BFA1 CTF18 GO:1903047 mitotic cell cycle process 3.58E-04 1.14E-02 2.14 (4334,263,177,23) RAD9 CLB5 CLB2 DCC1 SHE1 DPB11 DDC1 BRE1 HPC2 PAT1 NPR3 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 HDA1 SOH1 SMI1 NHP10 GO:0031323 regulation of cellular metabolic process 4.28E-11 1.85E-08 2.12 (4334,797,177,69) NUP133 BUB2 SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 NCB2 RXT3 UME6 SET3 GPB1 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 MRN1 CLB5 CLB2 SRS2 DPB11 LSP1 BRE1 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 ELP3 CAF40 SPN1 NCB2 RXT3 GO:0006351 transcription, DNA-templated 1.44E-05 8.51E-04 2.12 (4334,393,177,34) ARP6 UME6 SET3 DST1 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 BRE1 HPC2 HDA1 SMI1 SOH1 NHP10

M. Dubarry et al. 41 SI RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 ELP3 CAF40 SPN1 NCB2 RXT3 GO:0097659 nucleic acid-templated transcription 1.44E-05 8.39E-04 2.12 (4334,393,177,34) ARP6 UME6 SET3 DST1 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 BRE1 HPC2 HDA1 SMI1 SOH1 NHP10 NPR3 UBA4 LTE1 BUB2 PCP1 SLT2 PPH21 ASF1 RIM21 SIF2 SNT1 ARC18 NCB2 UME6 SET3 GO:0051128 regulation of cellular component organization 1.65E-04 6.16E-03 2.12 (4334,300,177,26) DST1 AZF1 XRN1 RTF1 HOS2 BFA1 CLB5 CLB2 TCO89 DDC1 HDA1 RIM9 RAD24 RIM101 LGE1 CHS5 LTE1 BUB2 MRC1 SLT2 SAC3 PPH21 RAD50 RAD9 CTF18 CHK1 RIM21 SSO2 RAD52 RRD2 SAP190 CTF8 GO:0022402 cell cycle process 3.07E-06 2.04E-04 2.11 (4334,452,177,39) RAD17 CSM3 GCS1 BFA1 MMS22 SWF1 CLB5 CLB2 DCC1 SHE1 RAD57 DDC1 DPB11 BRE1 VPS13 HPC2 SOH1 XRS2 PAT1 HCR1 RIM101 LGE1 RRN9 CHS5 LTE1 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 HPC2 HDA1 SOH1 SMI1 NHP10 NUP133 BUB2 GO:0080090 regulation of primary metabolic process 1.59E-10 4.91E-08 2.10 (4334,782,177,67) SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 NCB2 RXT3 UME6 SET3 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 MRN1 CLB5 CLB2 SRS2 DPB11 LSP1 BRE1 PAT1 NPR3 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 CKB2 HIR2 CKB1 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 SIF2 VHS3 ELP3 CAF40 TIF5 ARP6 GIM3 GYP1 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 DIA2 SHE1 HPC2 HDA1 SOH1 SMI1 GO:0019222 regulation of metabolic process 1.90E-11 2.73E-08 2.07 (4334,877,177,74) NHP10 NUP133 BUB2 SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 SWD1 CDC33 SNT1 SPN1 NCB2 RXT3 RRD2 UME6 SET3 GPB1 DST1 AZF1 BRE2 XRN1 CSM3 HOS2 ARP4 GCS1 BFA1 MRN1 CLB5 CLB2 SRS2 DPB11 LSP1 BRE1 PAT1 NPR3 RIM101 LGE1 LTE1 MRC1 NUP188 TIM50 SHE4 ASF1 SIF2 ELP3 RAD52 VAM10 TIF5 TRS85 CTF8 SIR1 RTF1 MMS22 SWF1 HDA3 SGF29 DCC1 SHE1 RAD57 ILM1 HDA1 NHP10 GO:0006996 organelle organization 2.25E-09 3.47E-07 2.05 (4334,754,177,63) SOH1 VPS21 NUP133 XRS2 VPS30 BUB2 SLT2 SAC3 RAD50 RRM3 CTF18 ATG21 SWD3 SSO2 SWD1 SNT1 SPN1 ARC18 IES5 RRD2 UME6 SET3 RIM8 BRE2 XRN1 CSM3 HOS2 BFA1 ARP4 CLB2 VAC8 SRS2 DDC1 BRE1

M. Dubarry et al. 42 SI RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 ELP3 CAF40 SPN1 NCB2 RXT3 GO:0032774 RNA biosynthetic process 3.55E-05 1.70E-03 2.03 (4334,410,177,34) ARP6 UME6 SET3 DST1 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 BRE1 HPC2 HDA1 SMI1 SOH1 NHP10 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 DPB3 VHS3 RAD52 ELP3 nucleobase-containing compound biosynthetic GO:0034654 2.85E-05 1.47E-03 1.91 (4334,514,177,40) CAF40 SPN1 NCB2 RXT3 ARP6 POL32 UME6 process SET3 DST1 CDC21 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 DPB2 BRE1 HPC2 HDA1 SMI1 NHP10 SOH1 PAT1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DCC1 RAD57 HPC2 HDA1 SOH1 SMI1 NHP10 XRS2 NUP133 GO:0090304 nucleic acid metabolic process 3.10E-11 1.91E-08 1.91 (4334,1062,177,83) UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 IES5 NCB2 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 PAT1 NPR3 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 PCP1 CKB2 HIR2 CKB1 YGR122W SOK2 EPS1 SWR1 RAD9 CHK1 ASF1 RIM21 SIF2 ELP3 CAF40 TIF5 ARP6 GIM3 SIR1 SWC5 RTF1 SRB2 SWF1 HDA3 SGF29 DIA2 HPC2 HDA1 VPS21 SOH1 SMI1 NHP10 NUP133 UBA4 TRR2 GO:0050794 regulation of cellular process 3.07E-10 7.37E-08 1.84 (4334,1107,177,83) BUB2 SLT2 SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 GET3 SWD1 CDC33 SNT1 SPN1 NCB2 RXT3 ARC18 UME6 SAP190 SET3 GPB1 DST1 AZF1 DCR2 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 MRN1 CLB5 CLB2 TCO89 SRS2 DPB11 DDC1 LSP1 BRE1 PAT1 NPR3 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 PCP1 CKB2 HIR2 CKB1 YGR122W SOK2 EPS1 SWR1 RAD9 CHK1 ASF1 RIM21 SIF2 VHS3 ELP3 CAF40 TIF5 ARP6 GIM3 GYP1 SIR1 GO:0050789 regulation of biological process 5.33E-11 2.09E-08 1.83 (4334,1175,177,88) SWC5 RTF1 SRB2 SWF1 HDA3 SGF29 DIA2 SHE1 HPC2 HDA1 VPS21 SOH1 SMI1 NHP10 NUP133 UBA4 TRR2 BUB2 SLT2 SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 GET3 SWD1 CDC33 SNT1 SPN1 NCB2 RXT3 ARC18 RRD2

M. Dubarry et al. 43 SI UME6 SAP190 SET3 GPB1 DST1 AZF1 DCR2 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 GCS1 MRN1 CLB5 CLB2 TCO89 SRS2 DPB11 DDC1 LSP1 BRE1 SRN2 NPR3 VPS30 MRL1 CHS5 SNX3 NUP188 SAC3 TIM50 VPS29 ATG21 INP52 VPS17 VPS8 GO:0015031 protein transport 8.36E-04 2.33E-02 1.81 (4334,406,177,30) SSO2 GET3 ELP3 VPS5 VPS55 TRS85 BPH1 SHR3 VPS71 RIM8 VPS60 GCS1 VID22 VPS13 VPS21 NUP133 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 SOK2 SWR1 ASF1 DPB3 ELP3 RAD52 CAF40 TIF5 ARP6 CTF8 SIR1 SWC5 RTF1 SRB2 HDA3 PSF1 GO:0034645 cellular macromolecule biosynthetic process 1.18E-05 7.17E-04 1.79 (4334,683,177,50) SGF29 DPB2 DCC1 HDA1 HPC2 SOH1 NHP10 SMI1 SAC3 RRM3 CTF18 ELF1 HTZ1 CDC33 SPN1 RXT3 NCB2 POL32 UME6 SET3 DST1 PSF2 AZF1 HOS2 ARP4 CLB5 DPB11 BRE1 UBA4 LGE1 SIW14 SLT2 CKB2 PPH21 URM1 CKB1 CHK1 ATG21 ASF1 SAF1 SWD3 SIF2 JJJ3 GO:0006464 cellular protein modification process 2.48E-04 8.59E-03 1.78 (4334,508,177,37) SWD1 ELP3 SNT1 RRD2 DPH2 SET3 GPB1 PKP1 PER1 DCR2 BRE2 DPH6 RTF1 HOS2 ARP4 SWF1 HDA3 SGF29 DPH5 DIA2 BRE1 HDA1 UBA4 LGE1 SIW14 SLT2 CKB2 PPH21 URM1 CKB1 CHK1 ATG21 ASF1 SAF1 SWD3 SIF2 JJJ3 GO:0036211 protein modification process 2.48E-04 8.52E-03 1.78 (4334,508,177,37) SWD1 ELP3 SNT1 RRD2 DPH2 SET3 GPB1 PKP1 PER1 DCR2 BRE2 DPH6 RTF1 HOS2 ARP4 SWF1 HDA3 SGF29 DPH5 DIA2 BRE1 HDA1 PAT1 NPR3 HCR1 LGE1 RIM101 RRN9 CHS5 LTE1 MRC1 PCP1 CKB2 HIR2 TIM50 CKB1 YGR122W SOK2 EPS1 SWR1 RAD9 CHK1 ASF1 RIM21 SIF2 VHS3 ELP3 RAD52 VPS5 CAF40 TIF5 ARP6 GIM3 GYP1 SIR1 SWC5 RTF1 SRB2 SWF1 HDA3 SGF29 DIA2 SHE1 RAD57 VPS13 HPC2 HDA1 VPS21 NHP10 SOH1 SMI1 XRS2 NUP133 GO:0065007 biological regulation 2.56E-11 2.77E-08 1.77 (4334,1330,177,96) UBA4 TRR2 BUB2 SLT2 SAC3 RAD50 PPH21 RRM3 ELF1 HTZ1 SWD3 GET3 SWD1 CDC33 SNT1 SPN1 NCB2 IES5 RXT3 ARC18 RRD2 UME6 SAP190 SET3 GPB1 PER1 DST1 AZF1 DCR2 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 GCS1 MRN1 CLB5 CLB2 TCO89 SRS2 DPB11 DDC1 LSP1 BRE1 PAT1 NPR3 HCR1 TRS20 LGE1 RIM101 CHS5 SIW14 LTE1 MRC1 GIM4 NUP188 HIR2 TIM50 GO:0016043 cellular component organization 3.36E-11 1.81E-08 1.77 (4334,1314,177,95) SHE4 SWR1 ASF1 DPB3 SIF2 PRE9 ELP3 RAD52 TIF5 VAM10 TRS85 ARP6 VPS71 CTF8 GIM3

M. Dubarry et al. 44 SI SIR1 SWC5 RTF1 SRB2 SWF1 HDA3 MMS22 SGF29 DPB2 DCC1 SHE1 RAD57 VPS13 HPC2 HDA1 ILM1 VPS21 NHP10 SOH1 SMI1 XRS2 NUP133 SRN2 VPS30 BUB2 SLT2 BEM1 SAC3 RAD50 PPH21 RRM3 CTF18 ELF1 ATG21 HTZ1 BUD27 SWD3 SSO2 GET3 SWD1 SAD1 SNT1 SPN1 NCB2 IES5 RXT3 ARC18 RRD2 BPH1 UME6 SET3 RIM8 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 GCS1 MRN1 CLB2 TCO89 VAC8 SRS2 DDC1 BRE1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 SOK2 SWR1 ASF1 DPB3 ELP3 RAD52 CAF40 TIF5 ARP6 CTF8 SIR1 SWC5 RTF1 SRB2 HDA3 PSF1 GO:0009059 macromolecule biosynthetic process 2.46E-05 1.28E-03 1.75 (4334,701,177,50) SGF29 DPB2 DCC1 HDA1 HPC2 SOH1 NHP10 SMI1 SAC3 RRM3 CTF18 ELF1 HTZ1 CDC33 SPN1 RXT3 NCB2 POL32 UME6 SET3 DST1 PSF2 AZF1 HOS2 ARP4 CLB5 DPB11 BRE1 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 DPB3 VHS3 RAD52 ELP3 CAF40 SPN1 NCB2 RXT3 ARP6 POL32 UME6 GO:0019438 aromatic compound biosynthetic process 2.17E-04 7.80E-03 1.74 (4334,562,177,40) SET3 DST1 CDC21 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 DPB2 BRE1 HPC2 HDA1 SMI1 NHP10 SOH1 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 DPB3 VHS3 RAD52 ELP3 CAF40 SPN1 NCB2 RXT3 ARP6 POL32 UME6 GO:0018130 heterocycle biosynthetic process 2.72E-04 9.05E-03 1.72 (4334,568,177,40) SET3 DST1 CDC21 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 DPB2 BRE1 HPC2 HDA1 SMI1 NHP10 SOH1 PAT1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 nucleobase-containing compound metabolic DCC1 RAD57 HPC2 HDA1 SOH1 SMI1 NHP10 GO:0006139 7.73E-09 9.54E-07 1.71 (4334,1219,177,85) XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 process RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 NCB2 IES5 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 GO:1901362 organic cyclic compound biosynthetic process 4.61E-04 1.43E-02 1.67 (4334,602,177,41) ELF1 ASF1 HTZ1 DPB3 VHS3 RAD52 ELP3

M. Dubarry et al. 45 SI CAF40 SPN1 NCB2 RXT3 ARP6 POL32 UME6 SET3 DST1 CDC21 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 DPB2 ERG3 BRE1 HPC2 HDA1 SMI1 NHP10 SOH1 UBA4 LGE1 SIW14 SLT2 CKB2 PPH21 URM1 CKB1 CHK1 ATG21 ASF1 SAF1 SWD3 SIF2 JJJ3 SWD1 TUM1 ELP3 SNT1 RRD2 DEG1 SAP190 GO:0043412 macromolecule modification 5.07E-04 1.54E-02 1.67 (4334,585,177,40) DPH2 SET3 GPB1 PKP1 PER1 DCR2 BRE2 DPH6 RTF1 HOS2 ARP4 SWF1 HDA3 DPH5 SGF29 DIA2 BRE1 HDA1 RIM101 LGE1 RRN9 SAC3 HIR2 SOK2 SWR1 ELF1 ASF1 HTZ1 DPB3 VHS3 RAD52 ELP3 cellular nitrogen compound biosynthetic GO:0044271 5.07E-04 1.53E-02 1.67 (4334,585,177,40) CAF40 SPN1 NCB2 RXT3 ARP6 POL32 UME6 process SET3 DST1 CDC21 AZF1 SIR1 SWC5 RTF1 SRB2 HOS2 ARP4 HDA3 SGF29 DPB2 BRE1 HPC2 HDA1 SMI1 SOH1 NHP10 NPR3 HCR1 RIM101 LGE1 LTE1 SIW14 MRC1 NUP188 HIR2 TIM50 SHE4 ASF1 RIM21 NOP4 SIF2 PRE9 ELP3 VAM10 CTF8 SIR1 HDA3 SGF29 DPB2 DCC1 RAD57 VPS13 ILM1 HDA1 SOH1 NHP10 VPS21 NUP133 VPS30 SAC3 RAD50 ELF1 ATG21 HTZ1 SSO2 GET3 SWD1 SNT1 SPN1 RXT3 NCB2 IES5 BPH1 RRD2 UME6 SET3 GO:0071840 cellular component organization or biogenesis 1.06E-09 1.99E-07 1.66 (4334,1434,177,97) RIM8 BRE2 ARP4 CLB2 SRS2 BRE1 PAT1 TRS20 CHS5 GIM4 SWR1 DPB3 RAD52 TIF5 TRS85 ARP6 VPS71 GIM3 SWC5 RTF1 SRB2 MMS22 SWF1 SHE1 HPC2 SMI1 XRS2 SRN2 BUB2 SLT2 BEM1 PPH21 RRM3 CTF18 BUD27 SWD3 SAD1 ARC18 XRN1 CSM3 HOS2 BFA1 GCS1 MRN1 TCO89 VAC8 DDC1 PAT1 HCR1 RIM101 LGE1 RRN9 HIR2 URM1 YGR122W SOK2 SWR1 ASF1 DPB3 NOP4 LSM1 ELP3 CAF40 LSM7 ARP6 SIR1 SWC5 RTF1 SRB2 HDA3 SGF29 HPC2 HDA1 SMI1 SOH1 NHP10 GO:0016070 RNA metabolic process 4.48E-05 2.00E-03 1.64 (4334,837,177,56) UBA4 LEA1 SLT2 SAC3 ELF1 HTZ1 TUM1 SAD1 CDC33 SPN1 NCB2 RXT3 DEG1 POL32 SAP190 UME6 SET3 DST1 AZF1 XRN1 NGL2 HOS2 ARP4 MRN1 DPB11 BRE1 IPK1 PAT1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 GO:0006725 cellular aromatic compound metabolic process 9.41E-08 9.24E-06 1.63 (4334,1280,177,85) CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DCC1 RAD57 HPC2 HDA1 SOH1 SMI1 NHP10

M. Dubarry et al. 46 SI XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 NCB2 IES5 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 PAT1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DCC1 RAD57 HPC2 HDA1 SOH1 SMI1 NHP10 GO:0046483 heterocycle metabolic process 1.14E-07 1.10E-05 1.62 (4334,1285,177,85) XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 NCB2 IES5 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 HCR1 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 SHE4 YGR122W EPS1 RAD9 ASF1 NOP4 SIF2 LSM1 PRE9 ELP3 CAF40 PKP1 CTF8 SIR1 PSF1 HDA3 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1 NHP10 SOH1 NUP133 UBA4 SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 PSF2 BRE2 ARP4 GO:0044260 cellular macromolecule metabolic process 5.36E-11 1.93E-08 1.59 (4334,1757,177,114) CLB5 SRS2 DPB11 BRE1 PAT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 ARP6 SHR3 GIM3 SWC5 RTF1 SRB2 SWF1 MMS22 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 SWD3 JJJ3 CDC33 SAD1 DEG1 POL32 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 VID22 DDC1 IPK1 PAT1 HCR1 LGE1 RIM101 RRN9 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 GO:1901360 organic cyclic compound metabolic process 2.74E-07 2.51E-05 1.58 (4334,1330,177,86) RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DCC1 RAD57 ERG3 HPC2 HDA1 SOH1 SMI1 NHP10 XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3

M. Dubarry et al. 47 SI SWD1 TUM1 CDC33 SAD1 SPN1 NCB2 IES5 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 HCR1 DFG16 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 LSM1 PRE9 ELP3 CAF40 PKP1 CTF8 SIR1 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1 NHP10 SOH1 NUP133 UBA4 SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 RIM8 GO:0043170 macromolecule metabolic process 2.59E-11 2.24E-08 1.57 (4334,1837,177,118) PSF2 BRE2 ARP4 CLB5 SRS2 DPB11 BRE1 RIM13 PAT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 ARP6 SHR3 GIM3 SWC5 RTF1 SRB2 MMS22 SWF1 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 SWD3 JJJ3 CDC33 SAD1 POL32 DEG1 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 VID22 DDC1 IPK1 PAT1 HCR1 LGE1 RIM101 RRN9 PCP1 MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 HDA3 PSF1 SGF29 DPB2 DCC1 RAD57 HPC2 HDA1 SOH1 SMI1 GO:0034641 cellular nitrogen compound metabolic process 3.80E-07 3.35E-05 1.57 (4334,1339,177,86) NHP10 XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 IES5 NCB2 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 HCR1 DFG16 LGE1 SIW14 PCP1 GIM4 CKB2 CKB1 URM1 EPS1 CHK1 ASF1 LAP2 SAF1 SIF2 PRE9 ELP3 TIF5 PKP1 SHR3 GIM3 RTF1 HDA3 SWF1 DPH5 SGF29 DIA2 HDA1 SRN2 UBA4 GO:0019538 protein metabolic process 7.45E-04 2.10E-02 1.49 (4334,905,177,55) SLT2 PPH21 ATG21 SWD3 GET3 SWD1 JJJ3 SAD1 CDC33 SNT1 RRD2 DPH2 SET3 VMS1 GPB1 PER1 RIM8 DCR2 BRE2 DPH6 HOS2 ARP4 VID22 BRE1 RIM13 GO:0006807 nitrogen compound metabolic process 1.09E-05 6.75E-04 1.46 (4334,1462,177,87) PAT1 HCR1 LGE1 RIM101 RRN9 CHS5 PCP1

M. Dubarry et al. 48 SI MRC1 HIR2 URM1 SHE4 YGR122W SOK2 SWR1 RAD9 CHK1 ASF1 DPB3 NOP4 VHS3 LSM1 ELP3 RAD52 CAF40 LSM7 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DCC1 RAD57 HPC2 HDA1 NHP10 SOH1 SMI1 XRS2 NUP133 UBA4 RAD24 SLT2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 TUM1 CDC33 SAD1 SPN1 NCB2 IES5 RXT3 UME6 SAP190 DEG1 POL32 SET3 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 SRS2 DPB11 DDC1 BRE1 IPK1 HCR1 RIM101 LGE1 RRN9 MRC1 HIR2 SOK2 SWR1 ASF1 LAP2 DPB3 VHS3 RAD52 ELP3 CAF40 TIF5 ARP6 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 HDA3 PSF1 DPH5 SGF29 DPB2 GO:0044249 cellular biosynthetic process 6.72E-04 1.92E-02 1.45 (4334,1030,177,61) DCC1 ERG3 HPC2 HDA1 SMI1 SOH1 NHP10 VPS30 SAC3 RRM3 CTF18 ELF1 HTZ1 JJJ3 CAT5 CDC33 SPN1 NCB2 RXT3 UME6 POL32 DPH2 SET3 DST1 PER1 PSF2 AZF1 DPH6 HOS2 ARP4 CLB5 DPB11 BRE1 HCR1 DFG16 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 VHS3 LSM1 PRE9 ELP3 CAF40 PKP1 CDC21 CTF8 SIR1 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1 NHP10 SOH1 NUP133 VPS30 UBA4 SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 RIM8 PSF2 BRE2 ARP4 GO:0044238 primary metabolic process 1.99E-06 1.39E-04 1.32 (4334,2327,177,125) CLB5 SRS2 DPB11 BRE1 RIM13 PAT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 ARP6 SHR3 GIM3 SWC5 RTF1 SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 INP52 SWD3 JJJ3 CAT5 CDC33 SAD1 POL32 DEG1 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 TCO89 VID22 DDC1 IPK1 HCR1 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 BET3 SHE4 YGR122W EPS1 RAD9 GO:0044237 cellular metabolic process 1.51E-06 1.07E-04 1.30 (4334,2423,177,129) ASF1 LAP2 NOP4 SIF2 VHS3 LSM1 PRE9 ELP3 CAF40 PKP1 CDC21 CTF8 SIR1 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1

M. Dubarry et al. 49 SI NHP10 SOH1 NUP133 VPS30 UBA4 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 PSF2 BRE2 ARP4 CLB5 SRS2 IPP1 DPB11 BRE1 PAT1 TRS20 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 TRS85 ARP6 SHR3 GIM3 SWC5 RTF1 SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 INP52 VIP1 SWD3 JJJ3 CAT5 CDC33 SAD1 POL32 DEG1 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 TCO89 VID22 VAC8 DDC1 IPK1 HCR1 DFG16 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 VHS3 LSM1 PRE9 ELP3 CAF40 PKP1 CDC21 CTF8 SIR1 PSF1 HDA3 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1 NHP10 SOH1 NUP133 VPS30 UBA4 SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 RIM8 PSF2 BRE2 ARP4 GO:0071704 organic substance metabolic process 1.71E-05 9.72E-04 1.27 (4334,2429,177,126) CLB5 SRS2 DPB11 BRE1 RIM13 PAT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 ARP6 SHR3 GIM3 SWC5 RTF1 SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 INP52 VIP1 SWD3 JJJ3 CAT5 CDC33 SAD1 POL32 DEG1 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 TCO89 VID22 DDC1 IPK1 HCR1 DFG16 RIM101 LGE1 SIW14 MRC1 PCP1 CKB2 HIR2 URM1 BET3 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 VHS3 LSM1 PRE9 ELP3 CAF40 PKP1 CDC21 CTF8 SIR1 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 HDA1 NHP10 SOH1 NUP133 VPS30 UBA4 TRR2 GO:0008152 metabolic process 4.83E-04 1.49E-02 1.19 (4334,2723,177,132) SAC3 RAD50 ELF1 ATG21 HTZ1 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 IES5 NCB2 RRD2 SAP190 UME6 SET3 DPH2 PER1 DST1 RIM8 PSF2 BRE2 ARP4 CLB5 SRS2 IPP1 DPB11 BRE1 RIM13 PAT1 TRS20 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 TRS85 ARP6 SHR3 GIM3 SWC5 RTF1

M. Dubarry et al. 50 SI SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 LEA1 SLT2 PPH21 RRM3 CTF18 INP52 VIP1 SWD3 JJJ3 CAT5 CDC33 SAD1 POL32 DEG1 VMS1 GPB1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 MRN1 TCO89 VID22 VAC8 DDC1 IPK1

Cellular components

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value GO:0008622 epsilon DNA polymerase complex 2.60E-04 9.32E-03 18.36 (4334,4,177,3) DPB2 DPB3 DPB11 GO:0030904 retromer complex 6.30E-04 1.87E-02 14.69 (4334,5,177,3) VPS5 VPS29 VPS17 GO:0034967 Set3 complex 8.55E-05 3.87E-03 13.99 (4334,7,177,4) HOS2 SNT1 SET3 SIF2 GO:0042575 DNA polymerase complex 1.66E-04 6.78E-03 12.24 (4334,8,177,4) DPB2 POL32 DPB11 DPB3 GO:0097346 INO80-type complex 8.22E-07 1.01E-04 11.43 (4334,15,177,7) SWR1 ARP4 IES5 ARP6 VPS71 NHP10 SWC5 GO:0000812 Swr1 complex 4.06E-05 2.91E-03 11.13 (4334,11,177,5) SWR1 ARP4 ARP6 VPS71 SWC5 GO:0043596 nuclear replication fork 2.88E-04 9.19E-03 10.88 (4334,9,177,4) CTF18 DIA2 MRC1 PSF2 GO:0005657 replication fork 5.25E-05 3.48E-03 8.16 (4334,18,177,6) CTF18 DIA2 MRC1 DPB11 PSF2 RRM3 GO:0070210 Rpd3L-Expanded complex 5.25E-05 3.23E-03 8.16 (4334,18,177,6) HOS2 SNT1 RXT3 UME6 SET3 SIF2 GO:0000118 histone deacetylase complex 2.33E-05 1.82E-03 6.32 (4334,31,177,8) HOS2 HDA3 SNT1 RXT3 UME6 SET3 HDA1 SIF2 GO:0070603 SWI/SNF superfamily-type complex 4.29E-04 1.32E-02 4.90 (4334,35,177,7) ARP4 SWR1 IES5 ARP6 VPS71 NHP10 SWC5 SRN2 VPS30 VPS60 MRL1 VPS5 TRS20 VPS55 GO:0044440 endosomal part 6.74E-05 3.41E-03 4.02 (4334,67,177,11) SNX3 VPS8 VPS21 BET3 SRN2 MRL1 VPS30 VPS5 VPS55 SNX3 VPS60 GO:0005768 endosome 1.88E-05 1.80E-03 3.69 (4334,93,177,14) GCS1 VPS29 ATG21 VPS17 VPS8 VPS13 VPS21 MRC1 RRM3 CTF18 SWR1 HTZ1 DPB3 SIF2 SET3 BRE1 SNT1 IES5 RXT3 ARP6 POL32 UME6 GO:0044454 nuclear chromosome part 1.49E-09 4.28E-07 3.40 (4334,216,177,30) HDA1 VPS71 PSF2 RAD17 SWC5 CSM3 HOS2 ARP4 PSF1 HDA3 DPB2 DIA2 DPB11 DDC1 NHP10 PAT1 RAD24 MRC1 RRM3 CTF18 SWR1 RAD9 GO:0044427 chromosomal part 2.69E-12 1.16E-09 3.34 (4334,293,177,40) HTZ1 DPB3 SWD3 SIF2 SWD1 SNT1 IES5 RXT3 ARP6 POL32 UME6 SET3 VPS71 CTF8 PSF2

M. Dubarry et al. 51 SI RAD17 BRE2 SIR1 SWC5 CSM3 RTF1 HOS2 PSF1 HDA3 ARP4 DPB2 DIA2 DCC1 DPB11 DDC1 BRE1 HDA1 NHP10 SNT1 NCB2 RXT3 UME6 SET3 PSF2 BRE2 RTF1 GO:0044451 nucleoplasm part 1.30E-06 1.39E-04 3.23 (4334,159,177,21) HOS2 SRB2 ARP4 PSF1 HDA3 SGF29 ELF1 DPB11 SWD3 SIF2 HDA1 SOH1 SWD1 VPS30 PPH21 ATG21 DPB3 SAF1 SWD3 SIF2 VHS3 SWD1 SNT1 IES5 RXT3 RRD2 POL32 GO:1902494 catalytic complex 1.82E-04 7.12E-03 2.07 (4334,319,177,27) UME6 SET3 BRE2 HOS2 ARP4 HDA3 MMS22 SGF29 DPB2 DIA2 DPB11 HDA1 NHP10 PAT1 NPR3 HCR1 TRS20 RRN9 CHS5 MRC1 GIM4 CKB2 NUP188 HIR2 TIM50 CKB1 BET3 SWR1 DPB3 SAF1 SIF2 VHS3 LSM1 PRE9 ELP3 VPS5 CAF40 TRS85 ARP6 VPS71 CTF8 GIM3 SIR1 SWC5 RTF1 SRB2 MMS22 HDA3 PSF1 SGF29 DPB2 DIA2 DCC1 SHE1 RAD57 HPC2 GO:0043234 protein complex 1.70E-13 1.46E-10 2.00 (4334,1089,177,89) HDA1 NHP10 SOH1 XRS2 NUP133 SRN2 VPS30 RAD24 BUB2 SAC3 RAD50 PPH21 CTF18 ELF1 VPS29 ATG21 HTZ1 VPS17 VPS8 SWD3 GET3 SWD1 CDC33 SNT1 IES5 NCB2 RXT3 ARC18 VPS55 RRD2 UME6 POL32 VMS1 SET3 PSF2 RAD17 BRE2 XRN1 CSM3 HOS2 ARP4 BFA1 TCO89 VAC8 DPB11 DDC1 RRN9 MRC1 NUP188 CKB2 CKB1 SWR1 DPB3 NOP4 SIF2 RAD52 LSM7 ARP6 VPS71 CDC21 SIR1 SWC5 RTF1 SRB2 PSF1 HDA3 SGF29 DPB2 DIA2 SHE1 RAD57 HDA1 SOH1 NHP10 GO:0044428 nuclear part 2.01E-05 1.73E-03 1.68 (4334,815,177,56) NUP133 XRS2 LEA1 SAC3 RAD50 RRM3 CTF18 ELF1 HTZ1 SWD3 SWD1 SAD1 SNT1 NCB2 IES5 RXT3 POL32 UME6 SET3 PSF2 RAD17 BRE2 CSM3 HOS2 ARP4 DDC1 DPB11 BRE1 NPR3 HCR1 MRC1 NUP188 CKB2 HIR2 BET3 TIM50 RAD9 NOP4 SIF2 MTC1 VHS3 LSM1 PRE9 ELP3 CAF40 VPS5 CTF8 SIR1 HDA3 PSF1 SGF29 DPB2 DIA2 DCC1 RAD57 HDA1 SOH1 NHP10 NUP133 VPS30 SAC3 RAD50 ELF1 1.62 ATG21 HTZ1 VPS8 GET3 SWD1 SNT1 RXT3 IES5 GO:0032991 macromolecular complex 1.65E-09 3.55E-07 NCB2 RRD2 UME6 SET3 PSF2 BRE2 ARP4 (4334,1512,177,100) DPB11 BRE1 PAT1 TRS20 RRN9 CHS5 GIM4 CKB1 SWR1 DPB3 SAF1 TIF5 LSM7 TRS85 ARP6 VPS71 GIM3 SWC5 RTF1 SRB2 MMS22 SHE1 HPC2 XRS2 SRN2 RAD24 BUB2 LEA1 PPH21 RRM3 CTF18 VPS29 VPS17 BUD27 SWD3 SAD1 CDC33 VPS55 ARC18 POL32 VMS1 RAD17 XRN1

M. Dubarry et al. 52 SI CSM3 HOS2 BFA1 MRN1 TCO89 VAC8 DDC1 PAT1 RIM101 LGE1 MIT1 RRN9 MRC1 NUP188 HIR2 URM1 YGR122W SOK2 RAD9 SWR1 CHK1 ASF1 LAP2 DPB3 NOP4 SIF2 LSM1 PRE9 RAD52 ELP3 CAF40 LSM7 ARP6 VPS71 CDC21 CTF8 SIR1 SWC5 RTF1 SRB2 MMS22 PSF1 HDA3 SGF29 DPB2 DIA2 RAD57 HPC2 HDA1 SMI1 GO:0005634 nucleus 7.25E-05 3.46E-03 1.38 (4334,1597,177,90) SOH1 NHP10 NUP133 XRS2 RAD24 LEA1 SLT2 SAC3 RAD50 PPH21 RRM3 CTF18 ELF1 HTZ1 SWD3 JJJ3 SWD1 CDC33 SAD1 SNT1 SPN1 NCB2 IES5 RXT3 POL32 DEG1 UME6 DST1 PSF2 AZF1 RAD17 BRE2 XRN1 NGL2 CSM3 HOS2 ARP4 MRN1 CLB5 CLB2 SRS2 IPP1 VID22 DPB11 DDC1 BRE1 IPK1 NPR3 SNX3 MRC1 PCP1 NUP188 CKB2 TIM50 BET3 EPS1 RAD9 NOP4 SIF2 MTC1 VPS5 VAM10 PKP1 CDC21 CTF8 GYP1 SIR1 VPS60 PSF1 HDA3 SGF29 DPB2 DIA2 DCC1 RAD57 HDA1 ILM1 VPS21 NHP10 SOH1 NUP133 VPS30 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 GET3 1.29 SWD1 SNT1 RXT3 NCB2 IES5 UME6 SET3 PER1 GO:0044446 intracellular organelle part 1.62E-04 6.97E-03 PSF2 BRE2 ARP4 YSP1 CLB2 DPB11 BRE1 PAT1 (4334,2011,177,106) MRL1 TRS20 RRN9 CHS5 CKB1 SWR1 DPB3 RAD52 TIF5 TRS85 LSM7 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 SWF1 SHE1 ERG3 XRS2 SRN2 RAD24 BUB2 ESBP6 LEA1 RRM3 CTF18 INP52 YSC83 SWD3 CAT5 SAD1 ARC18 VPS55 POL32 VMS1 RAD17 XRN1 CSM3 HOS2 GCS1 BFA1 TCO89 VAC8 DDC1 LSP1 NPR3 SNX3 MRC1 PCP1 NUP188 CKB2 TIM50 BET3 EPS1 RAD9 NOP4 SIF2 MTC1 VPS5 VAM10 PKP1 CDC21 CTF8 GYP1 SIR1 VPS60 PSF1 HDA3 SGF29 DPB2 DIA2 DCC1 RAD57 HDA1 ILM1 VPS21 NHP10 SOH1 NUP133 VPS30 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 GET3 1.28 SWD1 SNT1 RXT3 NCB2 IES5 UME6 SET3 PER1 GO:0044422 organelle part 2.16E-04 8.08E-03 PSF2 BRE2 ARP4 YSP1 CLB2 DPB11 BRE1 PAT1 (4334,2023,177,106) MRL1 TRS20 RRN9 CHS5 CKB1 SWR1 DPB3 RAD52 TIF5 TRS85 LSM7 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 SWF1 SHE1 ERG3 XRS2 SRN2 RAD24 BUB2 ESBP6 LEA1 RRM3 CTF18 INP52 YSC83 SWD3 CAT5 SAD1 ARC18 VPS55 POL32 VMS1 RAD17 XRN1 CSM3 HOS2 GCS1 BFA1 TCO89 VAC8 DDC1 LSP1

M. Dubarry et al. 53 SI NPR3 RIM101 LGE1 SNX3 PCP1 MRC1 NUP188 HIR2 URM1 BET3 TIM50 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 MTC1 LSM1 PRE9 ELP3 VPS5 CAF40 VAM10 MID1 PKP1 CDC21 ATO2 CTF8 GYP1 SIR1 VPS60 PSF1 HDA3 SGF29 DPB2 DIA2 RAD57 VPS13 ILM1 HDA1 VPS21 NHP10 SOH1 NUP133 VPS30 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 BPH1 UME6 1.21 GO:0043231 intracellular membrane-bounded organelle 5.60E-05 3.21E-03 PER1 DST1 PSF2 BRE2 ARP4 CLB5 YSP1 CLB2 (4334,2824,177,139) SRS2 IPP1 DPB11 BRE1 PAT1 MRL1 TRS20 RRN9 MIT1 CHS5 SOK2 SWR1 CHK1 DPB3 RAD52 LSM7 TRS85 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 ESBP6 LEA1 SLT2 BEM1 PPH21 RRM3 CTF18 VPS29 VPS17 YSC83 SWD3 JJJ3 CAT5 CDC33 SAD1 VPS55 ARC18 POL32 DEG1 VMS1 AZF1 RAD17 XRN1 NGL2 CSM3 HOS2 GCS1 MRN1 TCO89 VID22 VAC8 DDC1 LSP1 IPK1 NPR3 RIM101 LGE1 SNX3 PCP1 MRC1 NUP188 HIR2 URM1 BET3 TIM50 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 MTC1 LSM1 PRE9 ELP3 VPS5 CAF40 VAM10 MID1 PKP1 CDC21 ATO2 CTF8 GYP1 SIR1 VPS60 PSF1 HDA3 SGF29 DPB2 DIA2 RAD57 VPS13 ILM1 HDA1 VPS21 NHP10 SOH1 NUP133 VPS30 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 BPH1 UME6 1.21 GO:0043227 membrane-bounded organelle 5.60E-05 3.01E-03 PER1 DST1 PSF2 BRE2 ARP4 CLB5 YSP1 CLB2 (4334,2824,177,139) SRS2 IPP1 DPB11 BRE1 PAT1 MRL1 TRS20 RRN9 MIT1 CHS5 SOK2 SWR1 CHK1 DPB3 RAD52 LSM7 TRS85 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 MMS22 SWF1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 ESBP6 LEA1 SLT2 BEM1 PPH21 RRM3 CTF18 VPS29 VPS17 YSC83 SWD3 JJJ3 CAT5 CDC33 SAD1 VPS55 ARC18 POL32 DEG1 VMS1 AZF1 RAD17 XRN1 NGL2 CSM3 HOS2 GCS1 MRN1 TCO89 VID22 VAC8 DDC1 LSP1 IPK1 NPR3 RIM101 LGE1 SNX3 PCP1 MRC1 NUP188 1.16 GO:0043226 organelle 2.79E-04 9.60E-03 HIR2 URM1 BET3 TIM50 YGR122W EPS1 RAD9 (4334,3056,177,145) ASF1 LAP2 NOP4 SIF2 MTC1 LSM1 PRE9 ELP3 VPS5 CAF40 VAM10 MID1 PKP1 CDC21 ATO2

M. Dubarry et al. 54 SI CTF8 GYP1 SIR1 VPS60 HDA3 PSF1 SGF29 DDC1 DPB2 DIA2 RAD57 VPS13 ILM1 HDA1 IPK1 VPS21 SOH1 NHP10 NUP133 VPS30 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 LSP1 TUM1 SNT1 SPN1 RXT3 IES5 NCB2 BPH1 UME6 DST1 PER1 PSF2 BRE2 ARP4 CLB5 YSP1 CLB2 SRS2 IPP1 DPB11 BRE1 PAT1 MRL1 TRS20 RRN9 MIT1 CHS5 SOK2 SWR1 CHK1 DPB3 RAD52 LSM7 TRS85 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 MMS22 SWF1 SHE1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 BUB2 ESBP6 LEA1 SLT2 BEM1 PPH21 RRM3 CTF18 VPS29 INP52 VIP1 VPS17 BUD27 YSC83 SWD3 JJJ3 CAT5 CDC33 SAD1 VPS55 ARC18 POL32 DEG1 VMS1 AZF1 RAD17 XRN1 NGL2 CSM3 HOS2 BFA1 GCS1 MRN1 TCO89 VAC8 VID22 NPR3 RIM101 LGE1 SNX3 PCP1 MRC1 NUP188 HIR2 URM1 BET3 TIM50 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 SIF2 MTC1 LSM1 PRE9 ELP3 VPS5 CAF40 VAM10 MID1 PKP1 CDC21 ATO2 CTF8 GYP1 SIR1 VPS60 HDA3 PSF1 SGF29 IPK1 DPB2 DIA2 RAD57 VPS13 ILM1 HDA1 VPS21 SOH1 NHP10 NUP133 VPS30 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 TUM1 SNT1 SPN1 RXT3 NCB2 IES5 BPH1 UME6 1.16 GO:0043229 intracellular organelle 2.79E-04 9.23E-03 DST1 PER1 PSF2 BRE2 ARP4 CLB5 YSP1 CLB2 (4334,3056,177,145) SRS2 IPP1 DPB11 BRE1 PAT1 MRL1 TRS20 RRN9 MIT1 CHS5 SOK2 SWR1 CHK1 DPB3 LSP1 RAD52 LSM7 TRS85 ARP6 SHR3 VPS71 PET130 SWC5 RTF1 SRB2 MMS22 SWF1 SHE1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 BUB2 ESBP6 LEA1 SLT2 BEM1 PPH21 RRM3 CTF18 VPS29 INP52 VIP1 VPS17 BUD27 YSC83 SWD3 JJJ3 CAT5 CDC33 SAD1 VPS55 ARC18 POL32 DEG1 VMS1 AZF1 RAD17 XRN1 NGL2 CSM3 HOS2 BFA1 GCS1 MRN1 TCO89 VAC8 VID22 DDC1 NPR3 HCR1 LGE1 RIM101 SIW14 SNX3 LTE1 MRC1 PCP1 NUP188 CKB2 HIR2 TIM50 URM1 BET3 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 1.14 GO:0044424 intracellular part 3.05E-07 4.38E-05 NOP4 SIF2 MTC1 VHS3 LSM1 PRE9 ELP3 CAF40 (4334,3683,177,171) VPS5 VAM10 MID1 PKP1 CDC21 CTF8 ATO2 GYP1 SIR1 VPS60 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 VPS13 HDA1 ILM1 VPS21 NHP10 SOH1 NUP133 VPS30 UBA4 TRR2

M. Dubarry et al. 55 SI SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 TUM1 SNT1 SPN1 IES5 NCB2 RXT3 RRD2 BPH1 UME6 SAP190 DPH2 SET3 PER1 DST1 PSF2 BRE2 ARP4 YSP1 CLB5 CLB2 IPP1 SRS2 DPB11 BRE1 PAT1 MRL1 TRS20 MTC4 MIT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 TRS85 ARP6 YGR237C VPS71 SHR3 GIM3 PET130 SWC5 RTF1 SRB2 SWF1 MMS22 SHE1 ERG3 HPC2 SMI1 XRS2 SRN2 RAD24 BUB2 ESBP6 SLT2 LEA1 BEM1 PPH21 RRM3 AIM4 CTF18 VPS29 INP52 VIP1 VPS17 YSC83 BUD27 SWD3 JJJ3 CAT5 CDC33 SAD1 ARC18 VPS55 DEG1 POL32 VMS1 GPB1 NST1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 GCS1 BFA1 MRN1 TCO89 VAC8 VID22 ETP1 DDC1 LSP1 IPK1 NPR3 HCR1 DFG16 LGE1 RIM101 SIW14 SNX3 LTE1 MRC1 PCP1 NUP188 CKB2 HIR2 TIM50 URM1 BET3 SHE4 YGR122W EPS1 RAD9 ASF1 LAP2 NOP4 RIM21 SIF2 VHS3 MTC1 LSM1 PRE9 ELP3 CAF40 VPS5 VAM10 MID1 PKP1 CDC21 CTF8 ATO2 GYP1 SIR1 VPS60 HDA3 PSF1 SGF29 DPH5 DPB2 DIA2 DCC1 RAD57 VPS13 HDA1 ILM1 VPS21 NHP10 SOH1 NUP133 VPS30 UBA4 TRR2 SAC3 RAD50 ELF1 ATG21 HTZ1 VPS8 SSO2 GET3 SWD1 TUM1 SNT1 SPN1 IES5 NCB2 RXT3 RRD2 BPH1 UME6 SAP190 DPH2 1.11 SET3 PER1 DST1 RIM8 PSF2 BRE2 ARP4 YSP1 GO:0044464 cell part 9.82E-09 1.69E-06 CLB5 CLB2 IPP1 SRS2 DPB11 BRE1 RIM13 PAT1 (4334,3914,177,177) MRL1 TRS20 MTC4 MIT1 RRN9 CHS5 GIM4 CKB1 SOK2 SWR1 YDR090C CHK1 DPB3 SAF1 RAD52 TIF5 LSM7 TRS85 ARP6 YGR237C VPS71 SHR3 GIM3 PET130 SWC5 RTF1 SRB2 SWF1 MMS22 SHE1 ERG3 HPC2 SMI1 XRS2 SRN2 RIM9 RAD24 BUB2 ESBP6 SLT2 LEA1 BEM1 PPH21 RRM3 AIM4 CTF18 VPS29 INP52 VIP1 VPS17 YSC83 BUD27 SWD3 JJJ3 CAT5 CDC33 SAD1 ARC18 VPS55 DEG1 POL32 VMS1 GPB1 NST1 AZF1 DCR2 RAD17 XRN1 NGL2 DPH6 CSM3 HOS2 GCS1 BFA1 MRN1 TCO89 VAC8 VID22 ETP1 DDC1 LSP1 IPK1

M. Dubarry et al. 56 SI From positive genetic interactions:

Cellular processes

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value RPL29 RPL13A RPP1B RPL16A RPL9A RPS17B GO:0002181 cytoplasmic translation 8.42E-04 6.07E-01 3.56 (4331,92,119,9) RPS10A RPL24B RPL37B HUL5 VID30 UBP3 RPN6 RPN12 RPN14 GO:0006511 ubiquitin-dependent protein catabolic process 3.46E-04 7.50E-01 3.16 (4331,138,119,12) YDR161W RPT3 APC4 RPN7 YRB1 PRE2 modification-dependent protein catabolic GO:0019941 3.46E-04 5.00E-01 3.16 (4331,138,119,12) HUL5 VID30 UBP3 RPN6 RPN12 RPN14 process YDR161W RPT3 APC4 RPN7 YRB1 PRE2 proteolysis involved in cellular protein catabolic GO:0051603 6.19E-04 5.35E-01 2.97 (4331,147,119,12) HUL5 VID30 UBP3 RPN6 RPN12 RPN14 process YDR161W RPT3 APC4 RPN7 YRB1 PRE2 modification-dependent macromolecule GO:0043632 9.39E-04 5.80E-01 2.84 (4331,154,119,12) HUL5 VID30 UBP3 RPN6 RPN12 RPN14 catabolic process YDR161W RPT3 APC4 RPN7 YRB1 PRE2 RPL29 HUL5 SGF73 RPP1B GPI15 SDS3 YDR161W RPL9A RPS10A TIF6 RPL37B RCK1 MMS2 RPN6 PPT1 RPL16A ALG7 RPN14 GO:0019538 protein metabolic process 1.64E-04 7.12E-01 1.69 (4331,905,119,42) RPS17B PRE2 TAF12 HEM3 UBP3 RKM2 VID30 RPL13A BTN2 ALG6 RPT3 NOP1 APC4 FLC2 ARV1 ICP55 TFB4 RPN12 ATG16 YRB1 RPN7 DBF2 SUP45 RPL24B TFA2 RPL29 HUL5 PRP11 GPI15 PCF11 IRC5 RPL9A NOP56 RPL37B SWI4 RCK1 RAD10 RPA43 SSF1 PPT1 RPL16A RPN14 ALG7 PRE2 HEM3 UBP3 VID30 ULS1 BTN2 RGR1 NOP1 APC4 RPC17 TFB4 MAF1 RPN12 SNM1 YRB1 GO:0044260 cellular macromolecule metabolic process 5.79E-04 6.26E-01 1.37 (4331,1753,119,66) RPL24B RPP1B SGF73 RPC19 SDS3 YDR161W DBP3 RPS10A TIF6 MMS2 CIA1 RPN6 RTG2 TPA1 RPS17B MRT4 TAF12 RKM2 RPL13A PRP38 ALG6 SLX9 RPT3 PML1 FLC2 MCM3 ARV1 ATG16 RPN7 DBF2 TPP1 SUP45 RPL29 RPL13A RPP1B RPL16A RPL9A RPS17B GO:0002181 cytoplasmic translation 8.42E-04 6.07E-01 3.56 (4331,92,119,9) RPS10A RPL24B RPL37B

M. Dubarry et al. 57 SI Cellular components

FDR q- GO term Description P-value Enrichment (N, B, n, b) Genes value GO:0046695 SLIK (SAGA-like) complex 3.81E-04 5.48E-02 18.20 (4331,6,119,3) SGF73 RTG2 TAF12 HUL5 RPN6 RPN12 RPN14 RPT3 RPN7 GO:0000502 proteasome complex 3.52E-05 3.04E-02 7.28 (4331,35,119,7) PRE2 RPL29 RPL13A RPP1B RPL16A RPL9A RPL24B GO:0022625 cytosolic large ribosomal subunit 5.35E-04 6.60E-02 4.81 (4331,53,119,7) RPL37B RPL29 RPL13A RPP1B RPL16A RPL9A PUF6 GO:0015934 large ribosomal subunit 2.51E-04 5.41E-02 4.70 (4331,62,119,8) RPL24B RPL37B RPL29 RPL13A RPP1B RPL9A RPS10A RPL37B GO:0044445 cytosolic part 4.28E-05 1.85E-02 3.44 (4331,148,119,14) GCN1 CIA1 RPN6 RPN12 RPL16A RPS17B PRE2 RPL24B RPL29 RPP1B RPL13A RPL16A RPL9A RPS17B GO:0044391 ribosomal subunit 8.94E-04 9.64E-02 3.25 (4331,112,119,10) RPS10A PUF6 RPL24B RPL37B RPL29 PRP11 RPP1B DBP3 RPL9A YGR283C PUF6 RPS10A TIF6 NOP56 RPL37B SSF1 BRX1 GO:0030529 ribonucleoprotein complex 3.68E-04 6.36E-02 2.03 (4331,448,119,25) RPL16A RPS17B MRT4 AIM14 RPL13A PRP38 SLX9 NOP1 GCN1 SNM1 RPL24B SUP45 HUL5 RPL29 TFA2 PRP11 GPI15 PCF11 SEC20 RPL9A YGR283C PUF6 RPL37B NOP56 SWI4 SPO20 RAD10 RPA43 SSF1 BRX1 RPL16A ALG7 RPN14 PRE2 AIM14 VID30 RGR1 NOP1 APC4 TOM22 RPC17 TFB4 GUT2 RPN12 SNM1 GO:0032991 macromolecular complex 7.17E-05 2.06E-02 1.49 (4331,1512,119,62) RPL24B FIN1 SGF73 VTI1 RPP1B ORM1 RPC19 SDS3 DBP3 RPS10A TIF6 MMS2 CIA1 RPN6 RTG2 RPS17B MRT4 TAF12 RPL13A PRP38 PDX1 SLX9 RPT3 PML1 MCM3 GCN1 ATG16 RPN7 SUP45

M. Dubarry et al. 58 SI Table S6: Description of enhancers affecting defective DNA polymerase strains (q=0.05)

Negative interactors with Pol α, Pol δ and Pol ε Gene Systematic Description name name E3 ubiquitin ligase; forms heterodimer with Rad6p to regulate K63 polyubiquitination in response to oxidative stress and to monoubiquinate histone H2B-K123, which is required for the subsequent methylation of histone H3-K4 and H3-K79; required for BRE1 YDL074C DSBR, transcription, silencing, and checkpoint control; interacts with RNA-binding protein Npl3p, linking histone ubiquitination to mRNA processing; Bre1p-dependent histone ubiquitination promotes pre-mRNA splicing Component of the CCR4-NOT transcriptional complex; evolutionarily conserved; involved in controlling mRNA initiation, CAF40 YNL288W elongation, and degradation; binds Cdc39p DNA damage checkpoint protein; part of a PCNA-like complex required for DNA damage response, required for pachytene DDC1 YPL194W checkpoint to inhibit cell cycle in response to unrepaired recombination intermediates; potential Cdc28p substrate; forms nuclear foci upon DNA replication stress Histone variant H2AZ; exchanged for histone H2A in nucleosomes by the SWR1 complex; involved in transcriptional regulation through prevention of the spread of silent heterochromatin; Htz1p-containing nucleosomes facilitate RNA Pol II passage by HTZ1 YOL012C affecting correct assembly and modification status of RNA Pol II elongation complexes and by favoring efficient nucleosome remodeling Cytoplasmic inorganic pyrophosphatase (PPase); homodimer that catalyzes the rapid exchange of oxygens from Pi with water, IPP1 YBR011C highly expressed and essential for viability, active-site residues show identity to those from E. coli PPase Component of U2 snRNP complex; disruption causes reduced U2 snRNP levels; physically interacts with Msl1p; putative homolog LEA1 YPL213W of human U2A' snRNP protein Subunit of a heterodimeric NC2 transcription regulator complex; complex binds to TBP and can repress transcription by NCB2 YDR397C preventing preinitiation complex assembly or stimulate activated transcription; homologous to human NC2beta; complex also includes Bur6p Third subunit of DNA polymerase delta; involved in chromosomal DNA replication; required for error-prone DNA synthesis in the POL32 YJR043C presence of DNA damage and processivity; forms a complex with Rev3p, Rev7p and Pol31p; interacts with Hys2p, PCNA (Pol30p), and Pol1p DNA damage-dependent checkpoint protein; required for cell-cycle arrest in G1/S, intra-S, and G2/M, plays a role in postreplication repair (PRR) pathway; transmits checkpoint signal by activating Rad53p and Chk1p; hyperphosphorylated by RAD9 YDR217C Mec1p and Tel1p; multiple cyclin dependent kinase consensus sites and the C-terminal BRCT domain contribute to DNA damage checkpoint activation; Rad9p Chk1 Activating Domain (CAD) is phosphorylated at multiple sites by Cdc28p/Clb2p

M. Dubarry et al. 59 SI Checkpoint protein; involved in the activation of the DNA damage and meiotic pachytene checkpoints; with Mec3p and Ddc1p, RAD17 YOR368W forms a clamp that is loaded onto partial duplex DNA; homolog of human and S. pombe Rad1 and U. maydis Rec1 proteins Checkpoint protein; involved in the activation of the DNA damage and meiotic pachytene checkpoints; subunit of a clamp loader RAD24 YER173W that loads Rad17p-Mec3p-Ddc1p onto DNA; homolog of human and S. pombe Rad17 protein Subunit of MRX complex with Mre11p and Xrs2p; complex is involved in processing double-strand DNA breaks in vegetative cells, RAD50 YNL250W initiation of meiotic DSBs, telomere maintenance, and nonhomologous end joining; forms nuclear foci upon DNA replication stress Protein that stimulates strand exchange; stimulates strand exchange by facilitating Rad51p binding to single-stranded DNA; RAD52 YML032C anneals complementary single-stranded DNA; involved in the repair of double-strand breaks in DNA during vegetative growth and meiosis and UV induced sister chromatid recombination Protein that stimulates strand exchange; stimulates strand exchange by stabilizing the binding of Rad51p to single-stranded DNA; RAD57 YDR004W involved in the recombinational repair of double-strand breaks in DNA during vegetative growth and meiosis; forms heterodimer with Rad55p Endoplasmic reticulum packaging chaperone; required for incorporation of amino acid permeases into COPII coated vesicles for SHR3 YDL212W transport to the cell surface Protein involved in the regulation of cell wall synthesis; proposed to be involved in coordinating cell cycle progression with cell wall SMI1 YGR229C integrity Protein required for DNA repair; component of the Mre11 complex, which is involved in double strand breaks, meiotic XRS2 YDR369C recombination, telomere maintenance, and checkpoint signaling Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence YLR339C YLR339C data; partially overlaps the essential gene RPP0

Negative interactors with Pol δ Gene Systematic Description Name name Highly conserved iron-sulfur cluster binding protein; localized in the cytoplasm; forms a complex with Nbp35p that is involved in CFD1 YIL003W iron-sulfur protein assembly in the cytosol Protein involved in the synthesis of GlcNAc-PI; GlcNAc-PI is the first intermediate in the synthesis of glycosylphosphatidylinositol GPI15 YNL038W (GPI) anchors; homologous to the human PIG-H protein; GlcNAc-PI stands for N-acetylglucosaminyl phosphatidylinositol Transcription factor; component of the heteromeric Ino2p/Ino4p basic helix-loop-helix transcription activator that binds INO2 YDR123C inositol/choline-responsive elements (ICREs), required for derepression of phospholipid biosynthetic genes in response to inositol depletion; involved in diauxic shift

M. Dubarry et al. 60 SI V-ATPase assembly factor; functions with other V-ATPase assembly factors in the ER to efficiently assemble the V-ATPase PKR1 YMR123W membrane sector (V0); protein abundance increases in response to DNA replication stress High affinity Ca2+/Mn2+ P-type ATPase; required for Ca2+ and Mn2+ transport into Golgi; involved in Ca2+ dependent protein sorting, processing; D53A mutant (Mn2+ transporting) is rapamycin sensitive, Q783A mutant (Ca2+ transporting) is rapamycin PMR1 YGL167C resistant; Mn2+ transport into Golgi lumen required for rapamycin sensitivity; mutations in human homolog ATP2C1 cause acantholytic skin condition Hailey-Hailey disease; human ATP2C1 can complement yeast null mutant PRE8 YML092C Alpha 2 subunit of the 20S proteasome PRI1 YIR008C Subunit of DNA primase; DNA primase is required for DNA synthesis and double-strand break repair Strand exchange protein; forms a helical filament with DNA that searches for homology; involved in the recombinational repair of RAD51 YER095W double-strand breaks in DNA during vegetative growth and meiosis; homolog of Dmc1p and bacterial RecA protein DNA-dependent ATPase that stimulates strand exchange; modifies the topology of double-stranded DNA; involved in the RAD54 YGL163C recombinational repair of double-strand breaks in DNA during vegetative growth and meiosis; member of the SWI/SNF family of DNA translocases; forms nuclear foci upon DNA replication stress Protein that stimulates strand exchange; stimulates strand exchange by stabilizing the binding of Rad51p to single-stranded DNA; RAD55 YDR076W involved in the recombinational repair of double-strand breaks in DNA during vegetative growth and meiosis; forms heterodimer with Rad57p Subunit of heteropentameric Replication factor C (RF-C); RF-C is a DNA binding protein and ATPase that acts as a clamp loader RFC5 YBR087W of the proliferating cell nuclear antigen (PCNA) processivity factor for DNA polymerases delta and epsilon Subunit of the RecQ (Sgs1p) - Topo III (Top3p) complex; stimulates superhelical relaxing, DNA catenation/decatenation and ssDNA binding activities of Top3p; involved in response to DNA damage; functions in S phase-mediated cohesion establishment RMI1 YPL024W via a pathway involving the Ctf18-RFC complex and Mrc1p; stimulates Top3p DNA catenation/decatenation activity; null mutants display increased rates of recombination and delayed S phase YNL011C YNL011C Putative protein of unknown function; YNL011C is not an essential gene

Negative interactors with Pol α Systematic Gene name Description name

S-phase checkpoint protein required for DNA replication; couples DNA helicase and polymerase; interacts with and stabilizes :::MRC1*/ YCL060C*/ Pol2p at stalled replication forks during stress, where it forms a pausing complex with Tof1p and is phosphorylated by Mec1p;

MRC1 YCL061C defines a novel S-phase checkpoint with Hog1p that coordinates DNA replication and transcription upon osmostress; protects uncapped telomeres; Dia2p-dependent degradation mediates checkpoint recovery; mammalian claspin homolog

M. Dubarry et al. 61 SI Putative protein of unknown function; epitope-tagged protein localizes to the cytoplasm; YKR074W is not an essential gene; AIM29 YKR074W null mutant displays elevated frequency of mitochondrial genome loss Alanine transaminase (glutamic pyruvic transaminase); involved in alanine biosynthesis and catabolism; TOR1-independent ALT1 YLR089C role in determining chronological lifespan; expression is induced in the presence of alanine; repression is mediated by Nrg1p; ALT1 has a paralog, ALT2, that arose from the whole genome duplication; Alt2p is catalytically inactive Protein required for nuclear envelope morphology; nuclear pore complex localization, mRNA export from the nucleus; exhibits APQ12 YIL040W synthetic lethal genetic interactions with genes involved in lipid metabolism E2-like enzyme; involved in autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway; plays a role in formation of Atg8p-phosphatidylethanolamine conjugates, which are involved in membrane dynamics during autophagy and Cvt; interaction ATG3 YNR007C with Atg8p is regulated by its acetylation by Esa1p (catalytic subunit of NuA4 histone acetyltransferase complex) while attenuation of Atg3 acetylation is mediated by histone deacetylase Rpd3p Protein involved in transcription initiation; acts at TATA-containing promoters; associates with the basal transcription factor TFIID; contains two bromodomains; corresponds to the C-terminal region of mammalian TAF1; redundant with Bdf1p; protein BDF2 YDL070W abundance increases in response to DNA replication stress; BDF2 has a paralog, BDF1, that arose from the whole genome duplication Component of small ribosomal subunit (SSU) processosome; this complex contains U3 snoRNA; required at post- BUD21 YOR078W transcriptional step for efficient retrotransposition; absence results in decreased Ty1 Gag:GFP protein levels; originally isolated as bud-site selection mutant that displays a random budding pattern Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative BUD28 YLR062C sequence data; not conserved in closely related Saccharomyces species; 98% of ORF overlaps the verified gene RPL22A; diploid mutant displays a weak budding pattern phenotype in a systematic assay Chromatin remodeler that regulates various aspects of transcription; acts in in conjunction with Isw1b to regulate chromatin structure and maintain chromatin integrity during transcription elongation by RNAP II by preventing trans-histone exchange CHD1 YER164W over coding regions; contains a chromo domain, a helicase domain and a DNA-binding domain; component of both the SAGA and SLIK complexes Kinesin-associated protein; required for both karyogamy and mitotic spindle organization, interacts stably and specifically with CIK1 YMR198W Kar3p and may function to target this kinesin to a specific cellular role; locus encodes a long and short transcript with differing functions; CIK1 has a paralog, VIK1, that arose from the whole genome duplication Cdc42p-activated signal transducing kinase; member of the PAK (p21-activated kinase) family, along with Ste20p and Skm1p; CLA4 YNL298W involved in septin ring assembly, vacuole inheritance, cytokinesis, sterol uptake regulation; phosphorylates Cdc3p and Cdc10p; CLA4 has a paralog, SKM1, that arose from the whole genome duplication Chromatin-associated protein; required for sister chromatid cohesion; interacts with DNA polymerase alpha (Pol1p) and may CTF4 YPR135W link DNA synthesis to sister chromatid cohesion

M. Dubarry et al. 62 SI Nucleosomal histone H3-Lys79 methylase; methylation is required for telomeric silencing, meiotic checkpoint control, and DNA DOT1 YDR440W damage response eIF4E-associated protein, competes with eIF4G for binding to eIF4E; accelerates mRNA degradation by promoting decapping, facilitated by interaction with eIF4E; essential for Puf5p mediated repression; associates with Puf5p and Dhh1p; inhibits cap- EAP1 YKL204W dependent translation; functions independently of eIF4E to maintain genetic stability; plays a role in cell growth, implicated in the TOR signaling cascade Elongin C, conserved among eukaryotes; forms a complex with Cul3p that polyubiquitylates monoubiquitylated RNA ELC1 YPL046C polymerase II to trigger its proteolysis; plays a role in global genomic repair Subunit of hexameric RecA-like ATPase Elp456 Elongator subcomplex; which is required for modification of wobble ELP6 YMR312W nucleosides in tRNA; required for Elongator structural integrity Alpha subunit of cytoplasmic phenylalanyl-tRNA synthetase; forms a tetramer with Frs1p to form active enzyme; evolutionarily FRS2 YFL022C distant from mitochondrial phenylalanyl-tRNA synthetase based on protein sequence, but substrate binding is similar Multistep regulator of cAMP-PKA signaling; inhibits PKA downstream of Gpa2p and Cyr1p, thereby increasing cAMP GPB2 YAL056W dependency; inhibits Ras activity through direct interactions with Ira1p/2p; regulated by G-alpha protein Gpa2p; GPB2 has a paralog, GPB1, that arose from the whole genome duplication Subunit of the HIR complex; a nucleosome assembly complex involved in regulation of histone gene transcription; involved in HIR3 YJR140C position-dependent gene silencing and nucleosome reassembly; ortholog of human CABIN1 protein Transcriptional activator involved in maintenance of ion homeostasis; also involved in protection against DNA damage caused IMP2' YIL154C by bleomycin and other oxidants; contains a C-terminal leucine-rich repeat Lsm (Like Sm) protein; part of heteroheptameric complexes (Lsm2p-7p and either Lsm1p or 8p): cytoplasmic Lsm1p complex LSM6 YDR378C involved in mRNA decay; nuclear Lsm8p complex part of U6 snRNP and possibly involved in processing tRNA, snoRNA, and rRNA Mating pheromone alpha-factor, made by alpha cells; interacts with mating type a cells to induce cell cycle arrest and other MF(ALPHA)1 YPL187W responses leading to mating; also encoded by MF(ALPHA)2, although MF(ALPHA)1 produces most alpha-factor; MF(ALPHA)1 has a paralog, MF(ALPHA)2, that arose from the whole genome duplication MTC6 YHR151C Protein of unknown function; mtc6 is synthetically sick with cdc13-1 High affinity methionine permease; integral membrane protein with 13 putative membrane-spanning regions; also involved in MUP1 YGR055W cysteine uptake Protein related to mammalian high mobility group (HMG) proteins; nuclear protein; essential for function of H/ACA-type NHP2 YDL208W snoRNPs, which are involved in 18S rRNA processing PBY1 YBR094W Putative tubulin tyrosine ligase associated with P-bodies; forms cytoplasmic foci upon DNA replication stress PET20 YPL159C Mitochondrial protein; required for respiratory growth under some conditions and for stability of the mitochondrial genome

M. Dubarry et al. 63 SI Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative PSY1 YKL076C sequence data; not conserved in closely related Saccharomyces species; 69% of ORF overlaps the uncharacterized ORF YKL075C Pseudouridine synthase; catalyzes pseudouridylation at positions 35 and 56 in U2 snRNA, position 50 in 5S rRNA, position 13 in cytoplasmic tRNAs, and position 35 in pre-tRNA(Tyr); also pseudouridylates some mRNAs; relocates from nucleus to PUS7 YOR243C cytoplasm during heat shock and differentially modifies some mRNAs during heat shock; conserved in archaea, vertebrates, and some bacteria Cytoplasmic pre-60S factor; required for the correct recycling of shuttling factors Alb1, Arx1 and Tif6 at the end of the REI1 YBR267W ribosomal large subunit biogenesis; involved in bud growth in the mitotic signaling network Protein that binds to the Rap1p C-terminus; acts synergistically with Rif2p to help control telomere length and establish RIF1 YBR275C telomeric silencing; involved in control of DNA replication; contributes to resection of DNA double strand breaks (DSBs); deletion results in telomere elongation RNA polymerase II subunit B16; forms dissociable heterodimer with Rpb4p; Rpb4/7 dissociates from RNAPII as Ser2 CTD phosphorylation increases; Rpb4/7 regulates cellular lifespan via mRNA decay process; involved in recruitment of 3'-end RPB7 YDR404C processing factors to transcribing RNA polymerase II complex, export of mRNA to cytoplasm under stress conditions; also involved in translation initiation RNA polymerase III subunit C11; mediates pol III RNA cleavage activity and is important for termination of transcription; RPC11 YDR045C homologous to TFIIS Ribosomal 60S subunit protein L14A; N-terminally acetylated; homologous to mammalian ribosomal protein L14, no bacterial RPL14A YKL006W homolog; RPL14A has a paralog, RPL14B, that arose from the whole genome duplication Ribosomal 60S subunit protein L31B; associates with karyopherin Sxm1p; loss of both Rpl31p and Rpl39p confers lethality; RPL31B YLR406C homologous to mammalian ribosomal protein L31, no bacterial homolog; RPL31B has a paralog, RPL31A, that arose from the whole genome duplication Protein component of the small (40S) ribosomal subunit; RPS0B has a paralog, RPS0A, that arose from the whole genome RPS0B YLR048W duplication; required for maturation of 18S rRNA along with Rps0Ap; deletion of either RPS0 gene reduces growth rate, deletion of both genes is lethal; homologous to human ribosomal protein SA and bacterial S2 Ribosomal protein 10 (rp10) of the small (40S) subunit; homologous to mammalian ribosomal protein S3A, no bacterial RPS1B YML063W homolog; RPS1B has a paralog, RPS1A, that arose from the whole genome duplication Protein component of the small (40S) ribosomal subunit; overproduction suppresses mutations affecting RNA polymerase III- RPS20 YHL015W dependent transcription; homologous to mammalian ribosomal protein S20 and bacterial S10 Protein component of the small (40S) ribosomal subunit; mutation affects 20S pre-rRNA processing; homologous to RPS4A YJR145C mammalian ribosomal protein S4, no bacterial homolog; RPS4A has a paralog, RPS4B, that arose from the whole genome

M. Dubarry et al. 64 SI duplication Protein component of the small (40S) ribosomal subunit; homologous to mammalian ribosomal protein S9 and bacterial S4; RPS9B YBR189W RPS9B has a paralog, RPS9A, that arose from the whole genome duplication Peptidyl-prolyl cis/trans-isomerase; activator of the phosphotyrosyl phosphatase activity of PP2A; involved in G1 phase progression, microtubule dynamics, bud morphogenesis and DNA repair; required for rapid reduction of Sgs1p levels in RRD1 YIL153W response to rapamycin; subunit of the Tap42p-Sit4p-Rrd1p complex; protein increases in abundance and relative distribution to the nucleus increases upon DNA replication stress Component of the RSC chromatin remodeling complex; essential for viability and mitotic growth; homolog of SWI/SNF subunit RSC8 YFR037C Swi3p, but unlike Swi3p, does not activate transcription of reporters WD40 domain-containing protein involved in endosomal recycling; forms a complex with Rrt2p that functions in the retromer- RTT10 YPL183C mediated pathway for recycling internalized cell-surface proteins; interacts with Trm7p for 2'-O-methylation of N34 of substrate tRNAs; has a role in regulation of Ty1 transposition; human ortholog is WDR6 RecQ family nucleolar DNA helicase; role in genome integrity maintenance, chromosome synapsis, meiotic joint molecule/crossover formation; stimulates activity of Top3p; rapidly lost in response to rapamycin in Rrd1p-dependent manner; SGS1 YMR190C forms nuclear foci upon DNA replication stress; yeast SGS1 complements mutations in human homolog BLM implicated in Bloom syndrome; also similar to human WRN implicated in Werner syndrome; human BLM and WRN can each complement yeast null mutant Negative regulatory subunit of protein phosphatase 1 (Ppz1p); involved in coenzyme A biosynthesis; subunit of phosphopantothenoylcysteine decarboxylase (PPCDC: Cab3p, Sis2p, Vhs3p) complex and the CoA-Synthesizing Protein SIS2 YKR072C Complex (CoA-SPC: Cab2p, Cab3p, Cab4p, Cab5p, Sis2p and Vhs3p); SIS2 has a paralog, VHS3, that arose from the whole genome duplication Basic leucine zipper transcription factor of the ATF/CREB family; forms a complex with Tup1p and Cyc8p to both activate and SKO1 YNL167C repress transcription; cytosolic and nuclear protein involved in osmotic and oxidative stress responses Protein of unknown function; overexpression suppresses the growth defect of mutants lacking protein kinase A activity; SOK1 YDR006C involved in cAMP-mediated signaling; localized to the nucleus; similar to the mouse testis-specific protein PBS13 Protein involved in negative regulation of transcription; required for RNA polyadenylation; exhibits regulated interactions with SPT2 YER161C both histones and SWI-SNF components; relocalizes to the cytosol in response to hypoxia; similar to mammalian HMG1 proteins Hsp90 cochaperone; regulates spatial organization of amyloid-like proteins in the cytosol, thereby buffering the proteotoxicity STI1 YOR027W caused by amyloid-like proteins; interacts with the Ssa group of the cytosolic Hsp70 chaperones and activates Ssa1p ATPase activity; interacts with Hsp90 chaperones and inhibits their ATPase activity; homolog of mammalian Hop SUI2 YJR007W Alpha subunit of the translation initiation factor eIF2; eIF2 is involved in identification of the start codon; phosphorylation of

M. Dubarry et al. 65 SI Ser51 is required for regulation of translation by inhibiting the exchange of GDP for GTP; protein abundance increases in response to DNA replication stress Essential protein of the mitochondrial intermembrane space; forms a complex with Tim9p (TIM10 complex) that delivers TIM10 YHR005C-A hydrophobic proteins to the TIM22 complex for insertion into the inner membrane cAMP-dependent protein kinase catalytic subunit; promotes vegetative growth in response to nutrients via the Ras-cAMP TPK3 YKL166C signaling pathway; partially redundant with Tpk1p and Tpk2p; localizes to P-bodies during stationary phase; TPK3 has a paralog, TPK1, that arose from the whole genome duplication tRNA 2'-phosphotransferase that catalyzes final step in tRNA splicing: the transfer of the 2'-PO(4) from the splice junction to TPT1 YOL102C NAD(+) to form ADP-ribose 1''-2''cyclic phosphate and nicotinamide Catalytic subunit of adoMet-dependent tRNA methyltransferase complex; required for the methylation of the guanosine TRM11 YOL124C nucleotide at position 10 (m2G10) in tRNAs; contains a THUMP domain and a methyltransferase domain; another complex member is Trm112p Component of the nonsense-mediated mRNA decay (NMD) pathway; along with Nam7p and Nmd2p; involved in decay of UPF3 YGR072W mRNA containing nonsense codons; involved in telomere maintenance Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YBR099C YBR099C sequence data; completely overlaps the verified gene MMS4 Subunit of structure-specific Mms4p-Mus81p endonuclease; cleaves branched DNA; involved in recombination, DNA repair, YBR100W* MMS4 and joint molecule formation/resolution during meiotic recombination; phosphorylation of the non-catalytic subunit Mms4p by YBR098W Cdc28p and Cdc5p during mitotic cell cycle activates the function of Mms4p-Mus81p Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YJR087W YJR087W sequence data; not conserved in closely related Saccharomyces species; partially overlaps the verified genes STE18 and ECM2 Subunit of the heterohexameric Gim/prefoldin protein complex; involved in the folding of alpha-tubulin, beta-tubulin, and actin; YKE2 YLR200W prefoldin complex also localizes to chromatin of actively transcribed genes in the nucleus and facilitates transcriptional elongation Methionine-R-sulfoxide reductase; reduces the R enantiomer of free Met-SO, in contrast to Ycl033Cp which reduces Met-R- YKL069W YKL069W SO in a peptide linkage; has a role in protection against oxidative stress; relative distribution to the nucleus increases upon DNA replication stress Putative protein of unknown function; green fluorescent protein (GFP)-fusion protein localizes to the cytoplasm; proposed to be YKL075C YKL075C involved in resistance to streptozotocin and camptothecin Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YLR374C YLR374C sequence data; partially overlaps the uncharacterized ORF STP3/YLR375W

M. Dubarry et al. 66 SI YMD8 YML038C Putative nucleotide sugar transporter; has similarity to Vrg4p Transporter of the mitochondrial inner membrane that exports magnesium; involved in mitochondrial Mg2+ homeostasis; has YMR166C YMR166C similarity to human mitochondrial ATP-Mg/Pi carriers Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YMR245W YMR245W sequence data Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YNL171C YNL171C sequence data Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YOL134C YOL134C sequence data; partially overlaps HRT1, a verified gene that encodes an SCF ubiquitin ligase subunit Osmotic stress-responsive phosphorelay intermediate sensor protein; phosphorylated by the plasma membrane sensor Sln1p YPD1 YDL235C in response to osmotic stress and then in turn phosphorylates the response regulators Ssk1p in the cytosol and Skn7p in the nucleus Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative YPR050C YPR050C sequence data; almost completely overlaps verified ORF MAK3/YPR051W YPR153W YPR153W Putative protein of unknown function Rab family GTPase; Ras-like GTP binding protein involved in the secretory pathway, required for fusion of endosome-derived vesicles with the late Golgi, maturation of the vacuolar carboxypeptidase Y; resides temporarily at the Golgi, dissociates into YPT6 YLR262C cytosol upon arrival of the Rab GTPaseYpt32p, which also functions in the late Golgi; Golgi-localized form is bound to GTP, while cytosolic form is GDP-bound; homolog of the mammalian Rab6

Negative interactors with Pol ε Gene Systematic Description Name name Protein proposed to be associated with the nuclear pore complex; null mutant is viable, displays elevated frequency of AIM4 YBR194W mitochondrial genome loss and is sensitive to freeze-thaw stress ARC18 YLR370C Subunit of the ARP2/3 complex; ARP2/3 is required for the motility and integrity of cortical actin patches ARP4 YJL081C Nuclear actin-related protein involved in chromatin remodeling; component of chromatin-remodeling enzyme complexes Actin-related protein that binds nucleosomes; a component of the SWR1 complex, which exchanges histone variant H2AZ ARP6 YLR085C (Htz1p) for chromatin-bound histone H2A Phosphoinositide binding protein; required for vesicle formation in the cytoplasm-to-vacuole targeting (Cvt) pathway; binds both ATG21 YPL100W phosphatidylinositol (3,5)-bisphosphate and phosphatidylinositol 3-phosphate; WD-40 repeat protein

M. Dubarry et al. 67 SI Putative transmembrane protein involved in export of ammonia; ammonia is a starvation signal that promotes cell death in aging ATO2 YNR002C colonies; phosphorylated in mitochondria; member of the TC 9.B.33 YaaH family; homolog of Y. lipolytica Gpr1p; ATO2 has a paralog, ADY2, that arose from the whole genome duplication Zinc-finger transcription factor; involved in diauxic shift; in the presence of glucose, activates transcription of genes involved in AZF1 YOR113W growth and carbon metabolism; in nonfermentable carbon sources, activates transcription of genes involved in maintenance of cell wall integrity; relocalizes to the cytosol in response to hypoxia Protein containing SH3-domains; involved in establishing cell polarity and morphogenesis; functions as a scaffold protein for BEM1 YBR200W complexes that include Cdc24p, Ste5p, Ste20p, and Rsr1p Core component of transport protein particle (TRAPP) complexes I-III; TRAPP complexes are related multimeric guanine nucleotide-exchange factors for the GTPase Ypt1, regulating ER-Golgi traffic (TRAPPI), intra-Golgi traffic (TRAPPII), endosome- BET3 YKR068C Golgi traffic (TRAPPII and III) and autophagy (TRAPPIII); hydrophilic homodimeric protein that acts in conjunction with SNARE proteins in targeting and fusion of ER to Golgi transport vesicles Component of the GTPase-activating Bfa1p-Bub2p complex; involved in multiple cell cycle checkpoint pathways that control exit BFA1 YJR053W from mitosis; specifically required when telomeres are damaged, but not for all types of chromosomal DNA damage; phosphorylated by the Polo-like kinase Cdc5p Protein homologous to Chediak-Higashi syndrome and Beige proteins; both of which are implicated in disease syndromes in BPH1 YCR032W human and mouse, respectively, due to defective lysosomal trafficking; mutant phenotype and genetic interactions suggest a role in protein sorting Subunit of COMPASS (Set1C) complex; COMPASS methylates Lys4 of histone H3 and functions in silencing at telomeres; has a BRE2 YLR015W C-terminal Sdc1 Dpy-30 Interaction (SDI) domain that mediates binding to Sdc1p; similar to trithorax-group protein ASH2L Mitotic exit network regulator; forms GTPase-activating Bfa1p-Bub2p complex that binds Tem1p and spindle pole bodies, blocks BUB2 YMR055C cell cycle progression before anaphase in response to spindle and kinetochore damage Unconventional prefoldin protein involved in translation initiation; required for correct assembly of RNAP I, II, and III in an Rpb5p- dependent manner; shuttles between nucleus and cytoplasm; mutants have inappropriate expression of nutrient sensitive genes BUD27 YFL023W due to translational derepression of Gcn4p transcription factor; diploid mutants show random budding; ortholog of human URI/RMP Protein required for ubiquinone (Coenzyme Q) biosynthesis; localizes to the matrix face of the mitochondrial inner membrane in a CAT5 YOR125C large complex with ubiquinone biosynthetic enzymes; required for gluconeogenic gene activation CDC21 YOR074C Thymidylate synthase; required for de novo biosynthesis of pyrimidine deoxyribonucleotides; expression is induced at G1/S mRNA cap binding protein and translation initiation factor eIF4E; the eIF4E-cap complex is responsible for mediating cap- CDC33 YOL139C dependent mRNA translation via interactions with translation initiation factor eIF4G (Tif4631p or Tif4632p); protein abundance increases in response to DNA replication stress; mutants are defective for adhesion and pseudohyphal growth

M. Dubarry et al. 68 SI Serine/threonine kinase and DNA damage checkpoint effector; mediates cell cycle arrest via phosphorylation of Pds1p; CHK1 YBR274W phosphorylated by checkpoint signal transducer Mec1p; homolog of S. pombe and mammalian Chk1 checkpoint kinase Component of the exomer complex; exomer also contains Csh6p, Bch1p, Bch2p, and Bud7p and is involved in export of selected CHS5 YLR330W proteins, such as chitin synthase Chs3p, from the Golgi to the plasma membrane; Chs5p is the only protein with a BRCT domain that is not localized to the nucleus Beta regulatory subunit of casein kinase 2 (CK2); a Ser/Thr protein kinase with roles in cell growth and proliferation; CK2, CKB1 YGL019W comprised of CKA1, CKA2, CKB1 and CKB2, has many substrates including transcription factors and all RNA polymerases Beta' regulatory subunit of casein kinase 2 (CK2); a Ser/Thr protein kinase with roles in cell growth and proliferation; CK2, CKB2 YOR039W comprised of CKA1, CKA2, CKB1 and CKB2, has many substrates including transcription factors and all RNA polymerase B-type cyclin involved in cell cycle progression; activates Cdc28p to promote the transition from G2 to M phase; accumulates CLB2 YPR119W during G2 and M, then targeted via a destruction box motif for ubiquitin-mediated degradation by the proteasome; CLB2 has a paralog, CLB1, that arose from the whole genome duplication B-type cyclin involved in DNA replication during S phase; activates Cdc28p to promote initiation of DNA synthesis; functions in CLB5 YPR120C formation of mitotic spindles along with Clb3p and Clb4p; most abundant during late G1 phase; CLB5 has a paralog, CLB6, that arose from the whole genome duplication Subunit of a complex with Ctf8p and Ctf18p; shares some components with Replication Factor C; required for sister chromatid DCC1 YCL016C cohesion and telomere length maintenance Phosphoesterase; involved in downregulation of the unfolded protein response (UPR), at least in part via dephosphorylation of DCR2 YLR361C Ire1p; dosage-dependent positive regulator of the G1/S phase transition through control of the timing of START tRNA:pseudouridine synthase; introduces pseudouridines at position 38 or 39 in tRNA; also responsible for pseudouracil DEG1 YFL001W modification of some mRNAs; important for maintenance of translation efficiency and normal cell growth, localizes to both the nucleus and cytoplasm; non-essential for viability Probable multiple transmembrane protein; involved in diploid invasive and pseudohyphal growth upon nitrogen starvation; is DFG16 YOR030W glycosylated and phosphorylated; interacts with Rim21p and Rim9p in the plasma membrane to form a pH-sensing complex in the Rim101 pathway and is required to maintain Rim21p levels; required for accumulation of processed Rim101p Origin-binding F-box protein; forms SCF ubiquitin ligase complex with Skp1p and Cdc53p; functions in ubiquitylation of silent chromatin structural protein Sir4p; required to target Cdc6p for destruction during G1 phase; required for deactivation of Rad53 DIA2 YOR080W checkpoint kinase, completion of DNA replication during recovery from DNA damage, assembly of RSC complex, RSC-mediated transcription regulation, and nucleosome positioning; involved in invasive and pseudohyphal growth DNA replication initiation protein; loads DNA pol epsilon onto pre-replication complexes at origins; checkpoint sensor recruited to DPB11 YJL090C stalled replication forks by the checkpoint clamp complex where it activates Mec1p; along with Rfa1p, binds to ultrafine anaphase bridges in mitotic cells and prevents accumulation of chromatin bridges by stimulating the Mec1p kinase and suppressing

M. Dubarry et al. 69 SI homologous recombination; ortholog of human TopBP1; forms nuclear foci upon DNA replication stress Second largest subunit of DNA polymerase II (DNA polymerase epsilon); required for maintenance of fidelity of chromosomal DPB2 YPR175W replication; essential motif in C-terminus is required for formation of the four-subunit Pol epsilon; expression peaks at the G1/S phase boundary; Cdc28p substrate Third-largest subunit of DNA polymerase II (DNA polymerase epsilon); required to maintain fidelity of chromosomal replication and also for inheritance of telomeric silencing; stabilizes the interaction of Pol epsilon with primer-template DNA, positively DPB3 YBR278W affecting the processivity of the polymerase and exonuclease activities of Pol epsilon; mRNA abundance peaks at the G1/S boundary of the cell cycle; DPB3 has a paralog, DLS1, that arose from the whole genome duplication Protein required for synthesis of diphthamide; required along with Dph1p, Kti11p, Jjj3p, and Dph5p; diphthamide is a modified DPH2 YKL191W histidine residue of translation elongation factor 2 (Eft1p or Eft2p); may act in a complex with Dph1p and Kti11p Methyltransferase required for synthesis of diphthamide; diphthamide is a modified histidine residue of translation elongation DPH5 YLR172C factor 2 (Eft1p or Eft2p); not essential for viability; GFP-Dph5p fusion protein localizes to the cytoplasm Diphthamide synthetase; catalyzes the last amidation step of diphthamide biosynthesis using ammonium and ATP; evolutionarily conserved in eukaryotes; dph6 mutants exhibit diphthine accumulation and resistance to sordarin, which is indicative of defects in DPH6 YLR143W diphthamide formation on EF2; green fluorescent protein (GFP)-tagged protein localizes to the cytoplasm; DPH6/YLR143W is not an essential gene General transcription elongation factor TFIIS; enables RNA polymerase II to read through blocks to elongation by stimulating DST1 YGL043W cleavage of nascent transcripts stalled at transcription arrest sites; maintains RNAPII elongation activity on ribosomal protein genes during conditions of transcriptional stress Transcription elongation factor with a conserved zinc finger domain; implicated in the maintenance of proper chromatin structure ELF1 YKL160W in actively transcribed regions; deletion inhibits Brome mosaic virus (BMV) gene expression Subunit of Elongator complex; Elongator is required for modification of wobble nucleosides in tRNA; exhibits histone ELP3 YPL086C acetyltransferase activity that is directed to histones H3 and H4; disruption confers resistance to K. lactis zymotoxin ER protein with chaperone and co-chaperone activity; involved in retention of resident ER proteins; has a role in recognizing EPS1 YIL005W proteins targeted for ER-associated degradation (ERAD), member of the protein disulfide isomerase family C-5 sterol desaturase; glycoprotein that catalyzes the introduction of a C-5(6) double bond into episterol, a precursor in ergosterol ERG3 YLR056W biosynthesis; transcriptionally down-regulated when ergosterol is in excess; mutants are viable, but cannot grow on nonfermentable carbon sources; substrate of HRD ubiquitin ligase Protein with similarity to monocarboxylate permeases; appears not to be involved in transport of monocarboxylates such as ESBP6 YNL125C lactate, pyruvate or acetate across the plasma membrane Putative protein of unknown function required for growth on ethanol; contains a zinc finger region and has homology to human ETP1 YHL010C BRAP2, which is a cytoplasmic protein that binds nuclear localization sequences

M. Dubarry et al. 70 SI ADP-ribosylation factor GTPase activating protein (ARF GAP); involved in ER-Golgi transport; required for prospore membrane GCS1 YDL226C formation; regulates phospholipase Spo14p; shares functional similarity with Glo3p; GCS1 has a paralog, SPS18, that arose from the whole genome duplication Guanine nucleotide exchange factor for Gpa1p; amplifies G protein signaling; functions as a chaperone under ATP-depleted oxidative stress conditions; subunit of GET complex, involved in ATP dependent Golgi to ER trafficking and insertion of tail- GET3 YDL100C anchored (TA) proteins into ER membrane under non-stress conditions; binds as dimer to transmembrane domain (TMD) cargo, shielding TMDs from aqueous solvent; protein abundance increases under DNA replication stress Subunit of the heterohexameric cochaperone prefoldin complex; prefoldin binds specifically to cytosolic chaperonin and transfers GIM3 YNL153C target proteins to it; prefoldin complex also localizes to chromatin of actively transcribed genes in the nucleus and facilitates transcriptional elongation Multistep regulator of cAMP-PKA signaling; inhibits PKA downstream of Gpa2p and Cyr1p, thereby increasing cAMP GPB1 YOR371C dependency; promotes ubiquitin-dependent proteolysis of Ira2p; regulated by G-alpha protein Gpa2p; GPB1 has a paralog, GPB2, that arose from the whole genome duplication Cis-golgi GTPase-activating protein (GAP) for yeast Rabs; the Rab family members are Ypt1p (in vivo) and for Ypt1p, Sec4p, GYP1 YOR070C Ypt7p, and Ypt51p (in vitro); involved in vesicle docking and fusion eIF3j component of translation initiation factor 3 (eIF3); dual function protein involved in translation initiation as a substoichiometric component (eIF3j) of eIF3; required for processing of 20S pre-rRNA; required at post-transcriptional step for HCR1 YLR192C efficient retrotransposition; absence results in decreased Ty1 Gag:GFP protein levels; binds to eIF3 subunits Rpg1p and Prt1p and 18S rRNA Putative catalytic subunit of a class II histone deacetylase complex; role in azole resistance via Hsp90p, and in the heat shock HDA1 YNL021W response; Hda1p interacts with the Hda2p-Hda3p subcomplex to form an active tetramer; deletion increases histone H2B, H3 and H4 acetylation; other members of the HDA1 histone deacetylase complex are Hda2p and Hda3p Subunit of HIR nucleosome assembly complex; involved in regulation of histone gene transcription; recruits Swi-Snf complexes to HIR2 YOR038C histone gene promoters; promotes heterochromatic gene silencing with Asf1p; relocalizes to the cytosol in response to hypoxia Histone deacetylase and subunit of Set3 and Rpd3L complexes; required for gene activation via specific deacetylation of lysines HOS2 YGL194C in H3 and H4 histone tails; subunit of the Set3 complex, a meiotic-specific repressor of sporulation specific genes that contains deacetylase activity; co-localizes with Cmr1p in nuclear foci in response to DNA damage by MMS Protein of unknown function; may be involved in mitochondrial DNA maintenance; required for slowed DNA synthesis-induced ILM1 YJR118C filamentous growth Inositol 1,3,4,5,6-pentakisphosphate 2-kinase; nuclear protein required for synthesis of 1,2,3,4,5,6-hexakisphosphate (phytate), IPK1 YDR315C which is integral to cell function; has 2 motifs conserved in other fungi; ipk1 gle1 double mutant is inviable JJJ3 YJR097W Protein of unknown function; contains a CSL Zn finger and a DnaJ-domain; involved in diphthamide biosynthesis; ortholog human

M. Dubarry et al. 71 SI Dph4 Leucyl aminopeptidase yscIV with epoxide hydrolase activity; metalloenzyme containing one zinc atom; green fluorescent protein LAP2 YNL045W (GFP)-fusion protein localizes to the cytoplasm and nucleus; also known as leukotriene A4 hydrolase Lsm (Like Sm) protein; forms heteroheptameric complex (with Lsm2p, Lsm3p, Lsm4p, Lsm5p, Lsm6p, and Lsm7p) involved in degradation of cytoplasmic mRNAs; also enters the nucleus and positively regulates transcription initiation; unlike most Sm-like LSM1 YJL124C proteins, Lsm1p requires both its SM-domain and C-terminal domain for RNA-binding; binds to mRNAs under glucose starvation, most often in the 3' UTR; forms cytoplasmic foci upon DNA replication stress Eisosome core component; eisosomes are large immobile patch structures at the cell cortex associated with endocytosis; LSP1 YPL004C phosphorylated on Thr233 upon Pkc1p hyperactivation in a Slt2p MAPK-dependent fashion; null mutants show activation of Pkc1p/Ypk1p stress resistance pathways; member of the BAR domain family Protein similar to GDP/GTP exchange factors; without detectable GEF activity; required for asymmetric localization of Bfa1p at LTE1 YAL024C daughter-directed spindle pole bodies and for mitotic exit at low temperatures N-glycosylated integral membrane protein of the ER and plasma membrane; functions as a stretch-activated Ca2+-permeable MID1 YNL291C cation channel required for Ca2+ influx stimulated by pheromone; interacts with Cch1p; forms an oligomer Transcriptional regulator of pseudohyphal growth; protein with sequence similarity to S. pombe gti1+ (gluconate transport inducer MIT1 YEL007W 1) and C. albicans Wor1 Subunit of E3 ubiquitin ligase complex involved in replication repair; stabilizes protein components of the replication fork, such as MMS22 YLR320W the fork-pausing complex and leading strand polymerase, preventing fork collapse and promoting efficient recovery during replication stress; required for accurate meiotic chromosome segregation Membrane protein; has similarity to mammalian mannose-6-phosphate receptors; possibly functions as a sorting receptor in the MRL1 YPR079W delivery of vacuolar hydrolases; protein abundance increases in response to DNA replication stress RNA-binding protein that may be involved in translational regulation; binds specific categories of mRNAs, including those that MRN1 YPL184C contain upstream open reading frames (uORFs) and internal ribosome entry sites (IRES); interacts genetically with chromatin remodelers and splicing factors, linking chromatin state, splicing and as a result mRNA maturation Protein involved in 5.8S rRNA processing; Ccr4p-like RNase required for correct 3'-end formation of 5.8S rRNA at site E; similar NGL2 YMR285C to Ngl1p; NGL2 has a paralog, NGL3, that arose from the whole genome duplication Nucleolar protein; essential for processing and maturation of 27S pre-rRNA and large ribosomal subunit biogenesis; constituent of NOP4 YPL043W 66S pre-ribosomal particles; contains four RNA recognition motifs (RRMs) Subunit of the Iml1p/SEACIT complex; SEACIT (Iml1p-Npr2p-Npr3p) is a subcomplex of SEAC, a coatomer-related complex that associates dynamically with the vacuole; Npr3p may have a structural or regulatory role, supporting Iml1p function as a GAP for NPR3 YHL023C the Rag family GTPase Gtr1p, and leading to inhibition of TORC1 signaling in response to amino acid deprivation; SEACIT is required for non-nitrogen-starvation-induced autophagy; null mutant has meiotic defects; human NPRL3 homolog

M. Dubarry et al. 72 SI Subunit of Nup84p subcomplex of nuclear pore complex (NPC); contributes to nucleocytoplasmic transport, NPC biogenesis; is involved in establishment of a normal nucleocytoplasmic concentration gradient of GTPase Gsp1p; also plays roles in several NUP133 YKR082W processes that may require localization of genes or chromosomes at nuclear periphery, including double-strand break repair, transcription and chromatin silencing; relocalizes to cytosol in response to hypoxia; homolog of human NUP133 Subunit of the inner ring of the nuclear pore complex (NPC); contributes to NPC organization and nucleocytoplasmic transport; NUP188 YML103C homologous to human NUP188 Mitochondrial serine protease; required for the processing of various mitochondrial proteins and maintenance of mitochondrial PCP1 YGR101W DNA and morphology; belongs to the rhomboid-GlpG superfamily of intramembrane peptidases Protein of the endoplasmic reticulum; required for GPI-phospholipase A2 activity that remodels the GPI anchor as a prerequisite PER1 YCR044C for association of GPI-anchored proteins with lipid rafts; functionally complemented by human ortholog PERLD1 Protein required for respiratory growth; the authentic, non-tagged protein is detected in highly purified mitochondria in high- PET130 YJL023C throughput studies Mitochondrial protein kinase; involved in negative regulation of pyruvate dehydrogenase complex activity by phosphorylating the PKP1 YIL042C ser-133 residue of the Pda1p subunit; acts in concert with kinase Pkp2p and phosphatases Ptc5p and Ptc6p Alpha 3 subunit of the 20S proteasome; the only nonessential 20S subunit; may be replaced by the alpha 4 subunit (Pre6p) under PRE9 YGR135W stress conditions to create a more active proteasomal isoform Subunit of the GINS complex (Sld5p, Psf1p, Psf2p, Psf3p); complex is localized to DNA replication origins and implicated in PSF1 YDR013W assembly of the DNA replication machinery Subunit of the GINS complex (Sld5p, Psf1p, Psf2p, Psf3p); complex is localized to DNA replication origins and implicated in PSF2 YJL072C assembly of the DNA replication machinery Cys2His2 zinc-finger transcriptional repressor; involved in alkaline responsive gene repression as part of adaptation to alkaline RIM101 YHL027W conditions; involved in cell wall assembly; required for alkaline pH-stimulated haploid invasive growth and sporulation; activated by alkaline-dependent proteolytic processing which results in removal of the C-terminal tail; similar to A. nidulans PacC Calpain-like cysteine protease; involved in proteolytic activation of Rim101p in response to alkaline pH; localizes to punctate RIM13 YMR154C structures in alkaline conditions and in vps4 mutant; has similarity to A. nidulans palB pH sensor molecule, component of the RIM101 pathway; has a role in cell wall construction and alkaline pH response; is RIM21 YNL294C glycosylated and phosphorylated; interacts with Dfg16p and Rim9p to form a pH-sensing complex; localization to the plasma membrane is dependent on Dfg16p and Rim9p; has similarity to A. nidulans PalH Protein involved in proteolytic activation of Rim101p; part of response to alkaline pH; interacts with ESCRT-1 subunits Stp22p and RIM8 YGL045W Vps28p; essential for anaerobic growth; member of the arrestin-related trafficking adaptor family Plasma membrane protein of unknown function; involved in the proteolytic activation of Rim101p in response to alkaline pH; RIM9 YMR063W interacts with Rim21p and Dfg16p to form a pH-sensing complex in the Rim101 pathway and is required to maintain Rim21p

M. Dubarry et al. 73 SI levels; has similarity to A. nidulans PalI; DNA helicase involved in rDNA replication and Ty1 transposition; binds to and suppresses DNA damage at G4 motifs in vivo; RRM3 YHR031C relieves replication fork pauses at telomeric regions; structurally and functionally related to Pif1p RRN9 YMR270C Protein involved in promoting high level transcription of rDNA; subunit of UAF (upstream activation factor) for RNA polymerase I Component of the Rpd3L histone deacetylase complex; involved in histone deacetylation; protein abundance increases in RXT3 YDL076C response to DNA replication stress mRNA export factor; required for biogenesis of the small ribosomal subunit; component of TREX-2 complex (Sac3p-Thp1p- Sus1p-Cdc31p) involved in transcription elongation and mRNA export from the nucleus; involved in post-transcriptional tethering SAC3 YDR159W of active genes to the nuclear periphery and to non-nascent mRNP; similar to the human germinal center-associated nuclear protein (GANP) F-Box protein involved in proteasome-dependent degradation of Aah1p; involved in proteasome-dependent degradation of Aah1p SAF1 YBR280C during entry of cells into quiescence; interacts with Skp1 Protein that forms a complex with the Sit4p protein phosphatase; required for Sit4p function; member of a family of similar SAP190 YKR028W proteins including Sap4p, Sap155p, and Sap185p; SAP190 has a paralog, SAP185, that arose from the whole genome duplication Defining member of the SET3 histone deacetylase complex; which is a meiosis-specific repressor of sporulation genes; SET3 YKR029C necessary for efficient transcription by RNAPII; one of two yeast proteins that contains both SET and PHD domains; SET3 has a paralog, SET4, that arose from the whole genome duplication Component of the HAT/Core module of the SAGA, SLIK, and ADA complexes; HAT/Core module also contains Gcn5p, Ngg1p, SGF29 YCL010C and Ada2p; binds methylated histone H3K4; involved in transcriptional regulation through SAGA and TBP recruitment to target promoters and H3 acetylation Mitotic spindle protein; interacts with components of the Dam1 (DASH) complex, its effector Sli15p, and microtubule-associated SHE1 YBL031W protein Bim1p; also localizes to nuclear microtubules and to the bud neck in a ring-shaped structure; inhibits dynein function Protein containing a UCS (UNC-45/CRO1/SHE4) domain; binds to myosin motor domains to regulate myosin function; involved in SHE4 YOR035C endocytosis, polarization of the actin cytoskeleton, and asymmetric mRNA localization WD40 repeat-containing subunit of Set3C histone deacetylase complex; complex represses early/middle sporulation genes; SIF2 YBR103W antagonizes telomeric silencing; binds specifically to the Sir4p N-terminus Protein involved in silencing at mating-type loci HML and HMR; recruitment to silent chromatin requires interactions with Orc1p SIR1 YKR101W and with Sir4p, through a common Sir1p domain; binds to centromeric chromatin SIW14 YNL032W Tyrosine phosphatase involved in actin organization and endocytosis; localized to the cytoplasm Serine/threonine MAP kinase; involved in regulating maintenance of cell wall integrity, cell cycle progression, and nuclear mRNA SLT2 YHR030C retention in heat shock; required for mitophagy and pexophagy; affects recruitment of mitochondria to phagophore assembly site

M. Dubarry et al. 74 SI (PAS); plays a role in adaptive response of cells to cold; regulated by the PKC1-mediated signaling pathway; SLT2 has a paralog, KDX1, that arose from the whole genome duplication Subunit of the Set3C deacetylase complex; interacts directly with the Set3C subunit, Sif2p; putative DNA-binding protein; mutant SNT1 YCR033W has increased aneuploidy tolerance; relocalizes to the cytosol in response to hypoxia Sorting nexin for late-Golgi enzymes; required to maintain late-Golgi resident enzymes in their proper location by recycling SNX3 YOR357C molecules from the prevacuolar compartment; contains a PX domain and sequence similarity to human Snx3p Subunit of the RNA polymerase II mediator complex; associates with core polymerase subunits to form the RNA polymerase II SOH1 YGL127C holoenzyme; involved in telomere maintenance; conserved with other metazoan MED31 subunits Subunit of the RNA polymerase II mediator complex; associates with core polymerase subunits to form the RNA polymerase II SRB2 YHR041C holoenzyme; general transcription factor involved in telomere maintenance Component of the ESCRT-I complex; ESCRT-I is involved in ubiquitin-dependent sorting of proteins into the endosome; SRN2 YLR119W suppressor of rna1-1 mutation; may be involved in RNA export from nucleus Plasma membrane t-SNARE; involved in fusion of secretory vesicles at the plasma membrane; syntaxin homolog that is SSO2 YMR183C functionally redundant with Sso1p; SSO2 has a paralog, SSO1, that arose from the whole genome duplication Palmitoyltransferase that acts on transmembrane proteins; including the SNAREs Snc1p, Syn8p, Tlg1p and likely all SNAREs; SWF1 YDR126W contains an Asp-His-His-Cys-cysteine rich (DHHC-CRD) domain; may have a role in vacuole fusion Swi2/Snf2-related ATPase; structural component of the SWR1 complex, which exchanges histone variant H2AZ (Htz1p) for SWR1 YDR334W chromatin-bound histone H2A; relocalizes to the cytosol in response to hypoxia; chronological aging factor that mediates lifespan extension by dietary restriction Mitochondrial thioredoxin reductase; involved in protection against oxidative stress, required with Glr1p to maintain the redox TRR2 YHR106W state of Trx3p; contains active-site motif (CAVC) present in prokaryotic orthologs; binds NADPH and FAD; TRR2 has a paralog, TRR1, that arose from the whole genome duplication Core component of transport protein particle (TRAPP) complexes I-III; TRAPPs are multimeric guanine nucleotide-exchange factors for GTPase Ypt1p, regulating ER-Golgi traffic (TRAPPI), intra-Golgi traffic (TRAPPII), endosome-Golgi traffic (TRAPPII TRS20 YBR254C and III) and autophagy (TRAPPIII); mutation leads to defects in endocytic recycling, block in sporulation/meiosis; mutations in human homolog TRAPPC2 cause spondyloepiphyseal dysplasia tarda, TRAPPC2 can complement yeast null mutant Component of transport protein particle (TRAPP) complex III; TRAPPIII is a multimeric guanine nucleotide-exchange factor for the TRS85 YDR108W GTPase Ypt1p, regulating endosome-Golgi traffic and required for membrane expansion during autophagy and the CVT pathway; directs Ypt1p to the PAS; late post-replication meiotic role Rhodanese domain sulfur transferase; accepts persulfite from Nfs1p and transfers it to Uba4p in the pathway for 2-thiolation of TUM1 YOR251C the wobble uridine base of tRNAs; also stimulates sulfur transfer by Nfs1p; may be mitochondrially localized UME6 YDR207C Rpd3L histone deacetylase complex subunit; key transcriptional regulator of early meiotic genes; involved in chromatin

M. Dubarry et al. 75 SI remodeling and transcriptional repression via DNA looping; binds URS1 upstream regulatory sequence, represses transcription by recruiting conserved histone deacetylase Rpd3p (through co-repressor Sin3p) and chromatin-remodeling factor Isw2p; couples metabolic responses to nutritional cues with initiation and progression of meiosis, forms compl Ubiquitin-like protein involved in thiolation of cytoplasmic tRNAs; receives sulfur from the E1-like enzyme Uba4p and transfers it URM1 YIL008W to tRNA; also functions as a protein tag with roles in nutrient sensing and oxidative stress response Phosphorylated and palmitoylated vacuolar membrane protein; interacts with Atg13p, required for the cytoplasm-to-vacuole VAC8 YEL013W targeting (Cvt) pathway; interacts with Nvj1p to form nucleus-vacuole junctions VAM10 YOR068C Protein involved in vacuole morphogenesis; acts at an early step of homotypic vacuole fusion that is required for vacuole tethering Negative regulatory subunit of protein phosphatase 1 Ppz1p; involved in coenzyme A biosynthesis; subunit of the VHS3 YOR054C phosphopantothenoylcysteine decarboxylase (PPCDC; Cab3p, Sis2p, Vhs3p) complex and the CoA-Synthesizing Protein Complex (CoA-SPC: Cab2p, Cab3p, Cab4p, Cab5p, Sis2p and Vhs3p) Glycosylated integral membrane protein localized to plasma membrane; plays a role in fructose-1,6-bisphosphatase (FBPase) VID22 YLR373C degradation; involved in FBPase transport from the cytosol to Vid (vacuole import and degradation) vesicles; VID22 has a paralog, ENV11, that arose from the whole genome duplication Inositol hexakisphosphate and inositol heptakisphosphate kinase; inositol heptakisphosphate (IP7) production is important for VIP1 YLR410W phosphate signaling; involved in cortical actin cytoskeleton function, and invasive pseudohyphal growth analogous to S. pombe asp1; inositol hexakisphosphate is also known as IP6 Protein involved in prospore membrane morphogenesis; heterooligomeric or homooligomeric complex; peripherally associated with membranes; involved in sporulation, vacuolar protein sorting, prospore membrane formation during sporulatoin, and protein- VPS13 YLL040C Golgi retention; homologous to human CHAC and COH1 which are involved in chorea acanthocytosis and Cohen syndrome, respectively Subunit of the membrane-associated retromer complex; essential for endosome-to-Golgi retrograde protein transport; peripheral VPS17 YOR132W membrane protein that assembles onto the membrane with Vps5p to promote vesicle formation; required for recruiting the retromer complex to the endosome membranes Endosomal Rab family GTPase; required for endocytic transport and sorting of vacuolar hydrolases; required for endosomal localization of the CORVET complex; required with YPT52 for MVB biogenesis and sorting; involved in autophagy and ionic VPS21 YOR089C stress tolerance; geranylgeranylation required for membrane association; protein abundance increases in response to DNA replication stress; mammalian Rab5 homolog; VPS21 has a paralog, YPT53, that arose from the whole genome duplication Subunit of the membrane-associated retromer complex; endosomal protein; essential for endosome-to-Golgi retrograde transport; VPS29 YHR012W forms a subcomplex with Vps35p and Vps26p that selects cargo proteins for endosome-to-Golgi retrieval Subunit of phosphatidylinositol (PtdIns) 3-kinase complexes I and II; Complex I is essential in autophagy, Complex II is required VPS30 YPL120W for vacuolar protein sorting; required for overflow degradation of misfolded proteins when ERAD is saturated; C-terminus has

M. Dubarry et al. 76 SI novel globular fold essential for autophagy through the targeting of the PI3-kinase complex I to the pre-autophagosomal structure; ortholog of higher eukaryote gene Beclin 1; human BECN1 can complement yeast null mutant Nexin-1 homolog; required for localizing membrane proteins from a prevacuolar/late endosomal compartment back to late Golgi; VPS5 YOR069W structural component of retromer membrane coat complex; forms a retromer subcomplex with Vps17p; required for recruiting the retromer complex to the endosome membranes; VPS5 has a paralog, YKR078W, that arose from the whole genome duplication Late endosomal protein involved in late endosome to vacuole transport; functional homolog of human obesity receptor gene- VPS55 YJR044C related protein (OB-RGRP) Protein involved in late endosome to vacuole transport; cytoplasmic and vacuolar membrane protein; required for normal filament VPS60 YDR486C maturation during pseudohyphal growth; may function in targeting cargo proteins for degradation; interacts with Vta1p Nucleosome-binding component of the SWR1 complex; SWR1 exchanges histone variant H2AZ (Htz1p) for chromatin-bound VPS71 YML041C histone H2A; required for vacuolar protein sorting Membrane-binding component of the CORVET complex; involved in endosomal vesicle tethering and fusion in the endosome to VPS8 YAL002W vacuole protein targeting pathway; interacts with Vps21p; contains RING finger motif Evolutionarily-conserved 5'-3' exonuclease; component of cytoplasmic processing (P) bodies involved in mRNA decay; also XRN1 YGL173C enters the nucleus and positively regulates transcription initiation and elongation; plays a role in microtubule-mediated processes, filamentous growth, ribosomal RNA maturation, and telomere maintenance; activated by the scavenger decapping enzyme Dcs1p YDR090C YDR090C Putative protein of unknown function YGL046W*/ Protein involved in proteolytic activation of Rim101p; part of response to alkaline pH; interacts with ESCRT-1 subunits Stp22p and RIM8 YGL045W Vps28p; essential for anaerobic growth; member of the arrestin-related trafficking adaptor family Protein that may be involved in pH regulation; probable ortholog of A. nidulans PalC, which is involved in pH regulation and binds YGR122W YGR122W to the ESCRT-III complex; null mutant does not properly process Rim101p and has decreased resistance to rapamycin; GFP-

fusion protein is cytoplasmic; relative distribution to cytoplasm increases upon DNA replication stress YGR237C YGR237C Putative protein of unknown function; green fluorescent protein (GFP)-fusion protein localizes to the cytoplasm

Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence YJL169W YJL169W data; partially overlaps the verified gene YJL168C/SET2 Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence YOL050C YOL050C data; overlaps verified gene GAL11; deletion confers sensitivity to 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) Non-essential mitochondrial protein of unknown function; mRNA induced during meiosis, peaking between mid to late prophase YSC83 YHR017W of meiosis I; similar to S. douglasii YSD83 Mitochondrial protein; potential role in promoting mitochondrial fragmentation during programmed cell death in response to high YSP1 YHR155W levels of alpha-factor mating pheromone or the drug amiodarone; YSP1 has a paralog, SIP3, that arose from the whole genome duplication

M. Dubarry et al. 77 SI

Negative interactors with Pol δ and Pol ε Gene Systematic Description name name Polyphosphatidylinositol phosphatase; dephosphorylates a number of phosphatidylinositol phosphates (PtdInsPs, PIPs) to PI; involved in INP52 YNL106C endocytosis; hyperosmotic stress causes translocation to actin patches; synaptojanin-like protein with a Sac1 domain; INP52 has a paralog, INP53, that arose from the whole genome duplication Protein of unknown function; null mutant forms abnormally large cells, and homozygous diploid null mutant displays delayed premeiotic LGE1 YPL055C DNA synthesis and reduced efficiency of meiotic nuclear division Conserved zinc-finger domain protein involved in pre-mRNA splicing; critical for splicing of nearly all intron-containing genes; required for SAD1 YFR005C assembly of U4 snRNA into the U4/U6 particle

Negative interactors with Pol α and Pol δ Gene Systematic Description Name name 14-3-3 protein, major isoform; controls proteome at post-transcriptional level, binds proteins and DNA, involved in regulation of exocytosis, vesicle transport, Ras/MAPK and rapamycin-sensitive signaling, aggresome formation, spindle position checkpoint; protein increases in abundance and relative BMH1 YER177W distribution to the nucleus increases upon DNA replication stress; antiapoptotic gene similar to human 14-3-3; BMH1 has a paralog, BMH2, that arose from whole genome duplication NMD2 YHR077C Protein involved in the nonsense-mediated mRNA decay (NMD) pathway; interacts with Nam7p and Upf3p; involved in telomere maintenance Ornithine decarboxylase; catalyzes the first step in polyamine biosynthesis; degraded in a proteasome-dependent manner in the presence of excess SPE1 YKL184W polyamines; deletion decreases lifespan, and increases necrotic cell death and ROS generation Protein that regulates telomeric length; protects telomeric ends in a complex with Cdc13p and Stn1p; similar to human Ten1 which is critical for the TEN1 YLR010C telomeric function of the CST (Cdc13p-Stn1p-Ten1p) complex YDR269C YDR269C Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence data

Negative interactors with Pol α and Pol ε Gene Systematic Description Name name Nucleosome assembly factor; involved in chromatin assembly and disassembly, anti-silencing protein that causes derepression of silent loci when ASF1 YJL115W overexpressed; plays a role in regulating Ty1 transposition; relocalizes to the cytosol in response to hypoxia

M. Dubarry et al. 78 SI Replication fork associated factor; required for stable replication fork pausing; component of the DNA replication checkpoint pathway; required CSM3 YMR048W for accurate chromosome segregation during meiosis; forms nuclear foci upon DNA replication stress Subunit of a complex with Ctf8p; shares some subunits with Replication Factor C and is required for sister chromatid cohesion; may have CTF18 YMR078C overlapping functions with Rad24p in the DNA damage replication checkpoint CTF8 YHR191C Subunit of a complex with Ctf18p; shares some subunits with Replication Factor C; required for sister chromatid cohesion Subunit of the heterohexameric cochaperone prefoldin complex; complex binds specifically to cytosolic chaperonin and transfers target proteins to GIM4 YEL003W it Subunit of the HDA1 histone deacetylase complex; possibly tetrameric trichostatin A-sensitive class II histone deacetylase complex contains HDA3 YPR179C Hda1p homodimer and an Hda2p-Hda3p heterodimer; required for the activity of the complex; relocalizes to the cytosol in response to hypoxia; similar to Hda2p Subunit of the HIR complex; HIR is a nucleosome assembly complex involved in regulation of histone gene transcription; mutants display HPC2 YBR215W synthetic defects with subunits of FACT, a complex that allows passage of RNA Pol II through nucleosomes IES5 YER092W Non-essential INO80 chromatin remodeling complex subunit; deletion affects telomere maintenance via recombination Lsm (Like Sm) protein; part of heteroheptameric complexes (Lsm2p-7p and either Lsm1p or 8p): cytoplasmic Lsm1p complex involved in mRNA LSM7 YNL147W decay; nuclear Lsm8p complex part of U6 snRNP and possibly involved in processing tRNA, snoRNA, and rRNA; protein abundance increases and forms cytoplasmic foci in response to DNA replication stress S-phase checkpoint protein required for DNA replication; couples DNA helicase and polymerase; interacts with and stabilizes Pol2p at stalled replication forks during stress, where it forms a pausing complex with Tof1p and is phosphorylated by Mec1p; defines a novel S-phase checkpoint MRC1 YCL061C with Hog1p that coordinates DNA replication and transcription upon osmostress; protects uncapped telomeres; Dia2p-dependent degradation mediates checkpoint recovery; mammalian claspin homolog Protein of unknown function that may interact with ribosomes; green fluorescent protein (GFP)-fusion protein localizes to the cytoplasm and to MTC1 YJL123C COPI-coated vesicles (early Golgi); mtc1 is synthetically lethal with cdc13-1 Protein of unknown function; required for normal growth rate at 15 degrees C; green fluorescent protein (GFP)-fusion protein localizes to the MTC4 YBR255W cytoplasm in a punctate pattern; mtc4 is synthetically sick with cdc13-1 Non-essential INO80 chromatin remodeling complex subunit; preferentially binds DNA ends, protecting them from exonucleatic cleavage; NHP10 YDL002C deletion affects telomere maintenance via recombination; related to mammalian high mobility group proteins Protein of unknown function; mediates sensitivity to salt stress; interacts physically with the splicing factor Msl1p and also displays genetic NST1 YNL091W interaction with MSL1 Deadenylation-dependent mRNA-decapping factor; also required for faithful chromosome transmission, maintenance of rDNA locus stability, and PAT1 YCR077C protection of mRNA 3'-UTRs from trimming; associated with topoisomerase II; binds to mRNAs under glucose starvation, most often in the 3' UTR; functionally linked to Pab1p; forms cytoplasmic foci upon DNA replication stress; phosphorylation by PKA inhibits P body foci formation

M. Dubarry et al. 79 SI Catalytic subunit of protein phosphatase 2A (PP2A); functionally redundant with Pph22p; methylated at C terminus; forms alternate complexes PPH21 YDL134C with several regulatory subunits; involved in signal transduction and regulation of mitosis; forms nuclear foci upon DNA replication stress; PPH21 has a paralog, PPH22, that arose from the whole genome duplication Peptidyl-prolyl cis/trans-isomerase; also activates the phosphotyrosyl phosphatase activity of protein phosphatase 2A (PP2A); regulates G1 phase RRD2 YPL152W progression, the osmoresponse, microtubule dynamics; subunit of the Tap42p-Pph21p-Rrd2p complex; protein abundance increases in response to DNA replication stress Subunit of RNAPII-associated chromatin remodeling Paf1 complex; regulates gene expression by directing cotranscriptional histone modification, influences transcription and chromatin structure through several independent functional domains; directly or indirectly regulates DNA-binding RTF1 YGL244W properties of Spt15p and relative activities of different TATA elements; involved in transcription elongation as demonstrated by the G-less-based run-on (GLRO) assay Nuclear protein that negatively regulates pseudohyphal differentiation; plays a regulatory role in the cyclic AMP (cAMP)-dependent protein SOK2 YMR016C kinase (PKA) signal transduction pathway; relocalizes to the cytosol in response to hypoxia; SOK2 has a paralog, PHD1, that arose from the whole genome duplication Protein involved in RNA polymerase II transcription; is constitutively recruited to the CYC1 promoter and is required for recruitment of SPN1 YPR133C chromatin remodeling factors for the expression of CYC1 gene; interacts genetically or physically with RNAP II, TBP, TFIIS, and chromatin remodelling factors; central domain highly conserved throughout eukaryotes; mutations confer an Spt- phenotype DNA helicase and DNA-dependent ATPase; involved in DNA repair and checkpoint recovery, needed for proper timing of commitment to SRS2 YJL092W meiotic recombination and transition from Meiosis I to II; blocks trinucleotide repeat expansion; affects genome stability; disassembles Rad51p nucleoprotein filaments during meiotic recombination; functional homolog of human RTEL1 Component of the SWR1 complex; complex exchanges histone variant H2AZ (Htz1p) for chromatin-bound histone H2A; protein abundance SWC5 YBR231C increases in response to DNA replication stress; relocalizes to the cytosol in response to hypoxia Subunit of the COMPASS (Set1C) complex; COMPASS methylates histone H3 on lysine 4 and is required in transcriptional silencing near SWD1 YAR003W telomeres; WD40 beta propeller superfamily member with similarity to mammalian Rbbp7 Essential subunit of the COMPASS (Set1C) complex; COMPASS methylates histone H3 on lysine 4 and is required in transcriptional silencing SWD3 YBR175W near telomeres; WD40 beta propeller superfamily member and ortholog of mammalian WDR5 Subunit of TORC1 (Tor1p or Tor2p-Kog1p-Lst8p-Tco89p); regulates global H3K56ac; TORC1 complex regulates growth in response to nutrient TCO89 YPL180W availability; cooperates with Ssd1p in the maintenance of cellular integrity; deletion strains are hypersensitive to rapamycin Translation initiation factor eIF5; functions both as a GTPase-activating protein to mediate hydrolysis of ribosome-bound GTP and as a GDP TIF5 YPR041W dissociation inhibitor to prevent recycling of eIF2 Essential component of the TIM23 complex; acts as receptor for the translocase of the inner mitochondrial membrane (TIM23) complex guiding TIM50 YPL063W incoming precursors from the TOM complex; may control the gating of the Tim23p-Tim17p channel UBA4 YHR111W E1-like protein that activates Urm1p before urmylation; also acts in thiolation of the wobble base of cytoplasmic tRNAs by adenylating and then

M. Dubarry et al. 80 SI thiolating Urm1p; receives sulfur from Tum1p Component of a Cdc48p-complex involved in protein quality control; exhibits cytosolic and ER-membrane localization, with Cdc48p, during normal growth, and contributes to ER-associated degradation (ERAD) of specific substrates at a step after their ubiquitination; forms a VMS1 YDR049W mitochondrially-associated complex with Cdc48p and Npl4p under oxidative stress that is required for ubiquitin-mediated mitochondria- associated protein degradation (MAD); conserved in C. elegans and humans Putative protein of unknown function; not conserved in closely related Saccharomyces species; 98% of ORF overlaps the verified gene YPT6; VPS63 YLR261C deletion causes a vacuolar protein sorting defect; decreased levels of protein in enolase deficient mutant Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence data; not YGL042C YGL042C conserved in closely related Saccharomyces species; deletion mutation blocks replication of Brome mosaic virus in S. cerevisiae, but this is likely due to effects on the overlapping gene DST1 Dubious open reading frame; unlikely to encode a functional protein, based on available experimental and comparative sequence data; partially YNL235C YNL235C overlaps the verified ORF SIN4/YNL236W, a subunit of the mediator complex YPL205C YPL205C Hypothetical protein; deletion of locus affects telomere length

Asterisks indicate an alias was used to derive the systematic name.

M. Dubarry et al. 81 SI Files S1‐S2 Available for download as Excel files at www.g3journal.org/lookup/suppl/doi:10.1534/g3.115.021493/‐/DC1

File S1: QFA results File S2: List of stripped genes

M. Dubarry et al. 82 SI