Table 1. A selection of eukaryotic with a role in the maintenance of genome integrity

Process S. cerevisiae Mammals Function Human Disease Cancer* GCR* HR*

Replication CAC1, 2, 3 CHAF1A,B,p48 Chromatin assembly high high 1, 2 ASF1 ASF1A Chromatin assembly high high 1, 2 TOP1 TOP1 I high 3 TOP2 TOP2 Topoisomerase II high 3

Replicative helicase 4, 5 MCM4 MCM4 yes high subunit

Origin Replication 6 ORC3/5 ORC3/6L high complex CDC6 CDC6 Replication Initiation high 7 CDC9 LIG1 Ligase I high 7, 8

POL1/ 7-10 POLA1/PRIM1,2 Polymerase α/Primase high high PRI1,2

Polymerase ε subunit, 6, 11 DPB11 TOBP11 high checkpoint mediator POL3/CDC2 POLD1 Polymerase δ high 7, 8 POL30 PCNA PCNA normal high 12, 13 RAD27 FEN1 Flap endonuclease high high 14-16 Replication Factor A, 14, RFA1,2,3 RPA70,32,14 yes high high 17-19 checkpoint signalling PIF1 PIF1 RNA-DNA helicase high 20, 21 RRM3 unknown DNA Helicase normal high 22-26 Clamp loader, 11, RFC1-5 RFC1-5 high high 20, 27 checkpoint Checkpoint PDS1 PDS1 Mitotic arrest high 11, 28

Damage checkpoint 11, 29 RAD9 unknown high high mediator 11, MEC1 ATR Transducer kinase Seckel syndrome high high 28, 30, 31 Ataxia TEL1 ATM Transducer kinase Telangiectasia yes high high 11, 28 (AT) CHK1 CHEK1 Effector kinase Rare tumours yes high 11 Li-Fraumeni RAD53 CHEK2 Effector kinase syndrome yes high 11 variant DUN1 unknown Effector kinase high high 11, 32 DDC1- RAD9-RAD1- 11 RAD17- PCNA-like complex high HUS1 MEC3

RFC-like, S-phase 11, 33 RAD24 RAD17 high high checkponit CTF18 CHTF18 RFC-like, Cohesion high 34 ELG1 unknown RFC-like high high 34-37 DDC2 ATRIP Signalling high high 11, 38 14, DSB 20, MRE11 MRE11 HR and NHEJ AT-like disease high high Repair 28, 39

Nijmegen 14, XRS2 NBS1 HR and NHEJ breakage yes high 20, 28 syndrome, NBS 14, RAD50 RAD50 HR and NHEJ high high 20, 28, 40 RAD52 RAD52 HR high 20

RAD51,54, 20 RAD51, 54L HR high 57, 59 Damage checkpoint Familial breast 41 BRCA1 yes high high mediator ovarian cancer

BRCA2/FANC- Repair of cross-links, Familial breast 42-44 yes high D2 HR cancer YKU70- 14, KU70-KU80 NHEJ high 20, 35 YKU80 DNL4 LIG4 NHEJ Lig4 syndrome high 14

Chromatin 45, 46 H2A H2AX high decondensation 8, 13, SRS2 FBH1 HR normal high 26, 47 TOP3 TOP3A,B HR high high 48, 49 28, BLM RecQ helicase Bloom syndrome yes high high 48-52

Werner 53, 54 WRN RecQ helicase yes high syndrome Other repair RAD5 unknown Postreplicative repair high high 37, 55 pathways 37, RAD18 RAD18 Postreplicative repair high high 55-57

MSH2 MSH2 MMR HNPCC yes high 49, 58

FANC A-G, D1/BRCA2, D2, cross-linkage repair Fanconi Anemia yes high high 59 L

HPR1- mRNP THO complex, mRNP 60-62 THO2-MFT1- THOC1-7 high biogenesis biogenesis THP2

mRNP biogenesis- 63, 64 SRB2-YRA1 UAP56-ALY high export

ASF2/SF2 pre-mRNA splicing high 65

THP1-SAC3 SACD1 mRNA export high 66, 67

RRP6 EXOSC10 Nuclear Exosome high 68

mRNA 3'-end 68 RNA14 CSTF3 high processing NAB2 NAB2 hnRNP high 67 Others TSA1 PRDX2 Thioredoxin peroxidase high 37, 58

Cell cycle regulator 7, 8 CDC5 CDC5L high kinase CDC13 CCNB1 Telomere capping high 7, 8

Cell cycle phosphatase, 7, 8 CDC14 CDC14B high mitotic exit YCS4 NCAPD2 Mitotic condensation high 58

SMC5-SMC6 SMC5-SMC6 Cohesion-related/repair high 69

70 SIC1 unknown G1-S transition high

The table lists those genes whose mutations have been shown to increase HR (Homologous recombination), GCR (Gross Chromosomal Rearrangements) or both, without specifying whether the increase is strong or weak. * Blank indicates that the effect in cancer predisposition, HR or GCR is not known.

1. Myung, K., Pennaneach, V., Kats, E.S. & Kolodner, R.D. chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability. Proc Natl Acad Sci U S A 100, 6640-5 (2003). 2. Prado, F., Cortes-Ledesma, F. & Aguilera, A. The absence of the yeast chromatin assembly factor Asf1 increases genomic instability and sister chromatid exchange. EMBO Rep 5, 497-502 (2004). 3. Christman, M.F., Dietrich, F.S. & Fink, G.R. Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA I and II. Cell 55, 413-25 (1988). 4. Liang, D.T., Hodson, J.A. & Forsburg, S.L. Reduced dosage of a single fission yeast MCM causes genetic instability and S phase delay. J Cell Sci 112 ( Pt 4), 559-67 (1999). 5. Shima, N. et al. A viable allele of Mcm4 causes instability and mammary adenocarcinomas in mice. Nat Genet 39, 93-8 (2007). 6. Huang, D. & Koshland, D. Chromosome integrity in Saccharomyces cerevisiae: the interplay of DNA replication initiation factors, elongation factors, and origins. Genes Dev 17, 1741-54 (2003). 7. Hartwell, L.H. & Smith, D. Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. Genetics 110, 381-95 (1985). 8. Aguilera, A. & Klein, H.L. Genetic control of intrachromosomal recombination in Saccharomyces cerevisiae. I. Isolation and genetic characterization of hyper- recombination mutations. Genetics 119, 779-90 (1988). 9. Lemoine, F.J., Degtyareva, N.P., Lobachev, K. & Petes, T.D. Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites. Cell 120, 587-98 (2005). 10. Longhese, M.P., Jovine, L., Plevani, P. & Lucchini, G. Conditional mutations in the yeast DNA primase genes affect different aspects of DNA metabolism and interactions in the DNA polymerase alpha-primase complex. Genetics 133, 183- 91 (1993). 11. Myung, K., Datta, A. & Kolodner, R.D. Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell 104, 397-408 (2001). 12. Chen, C., Merrill, B.J., Lau, P.J., Holm, C. & Kolodner, R.D. Saccharomyces cerevisiae pol30 (proliferating cell nuclear antigen) mutations impair replication fidelity and mismatch repair. Mol Cell Biol 19, 7801-15 (1999). 13. Motegi, A., Kuntz, K., Majeed, A., Smith, S. & Myung, K. Regulation of gross chromosomal rearrangements by ubiquitin and SUMO ligases in Saccharomyces cerevisiae. Mol Cell Biol 26, 1424-33 (2006). 14. Chen, C. & Kolodner, R.D. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nat Genet 23, 81-5 (1999). 15. Freudenreich, C.H., Kantrow, S.M. & Zakian, V.A. Expansion and length- dependent fragility of CTG repeats in yeast. Science 279, 853-6 (1998). 16. Tishkoff, D.X., Filosi, N., Gaida, G.M. & Kolodner, R.D. A novel mutation avoidance mechanism dependent on S. cerevisiae RAD27 is distinct from DNA mismatch repair. Cell 88, 253-63 (1997). 17. Chen, C., Umezu, K. & Kolodner, R.D. Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol Cell 2, 9-22 (1998). 18. Smith, J. & Rothstein, R. A mutation in the encoding the Saccharomyces cerevisiae single-stranded DNA-binding protein Rfa1 stimulates a RAD52- independent pathway for direct-repeat recombination. Mol Cell Biol 15, 1632-41 (1995). 19. Wang, Y. et al. Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. Nat Genet 37, 750-5 (2005). 20. Myung, K., Chen, C. & Kolodner, R.D. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411, 1073-6 (2001). 21. Schulz, V.P. & Zakian, V.A. The saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation. Cell 76, 145-55 (1994). 22. Ivessa, A.S. et al. The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol Cell 12, 1525-36 (2003). 23. Ivessa, A.S., Zhou, J.Q., Schulz, V.P., Monson, E.K. & Zakian, V.A. Saccharomyces Rrm3p, a 5' to 3' DNA helicase that promotes replication fork progression through telomeric and subtelomeric DNA. Genes Dev 16, 1383-96 (2002). 24. Ivessa, A.S., Zhou, J.Q. & Zakian, V.A. The Saccharomyces Pif1p DNA helicase and the highly related Rrm3p have opposite effects on replication fork progression in ribosomal DNA. Cell 100, 479-89 (2000). 25. Keil, R.L. & McWilliams, A.D. A gene with specific and global effects on recombination of sequences from tandemly repeated genes in Saccharomyces cerevisiae. Genetics 135, 711-8 (1993). 26. Schmidt, K.H. & Kolodner, R.D. Suppression of spontaneous genome rearrangements in yeast DNA helicase mutants. Proc Natl Acad Sci U S A 103, 18196-201 (2006). 27. Noskov, V.N., Araki, H. & Sugino, A. The RFC2 gene, encoding the third- largest subunit of the replication factor C complex, is required for an S-phase checkpoint in Saccharomyces cerevisiae. Mol Cell Biol 18, 4914-23 (1998). 28. Myung, K. & Kolodner, R.D. Suppression of genome instability by redundant S- phase checkpoint pathways in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 99, 4500-7 (2002). 29. Weinert, T.A. & Hartwell, L.H. Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage. Mol Cell Biol 10, 6554-64 (1990). 30. Casper, A.M., Nghiem, P., Arlt, M.F. & Glover, T.W. ATR regulates fragile site stability. Cell 111, 779-89 (2002). 31. Vallen, E.A. & Cross, F.R. Mutations in RAD27 define a potential link between G1 cyclins and DNA replication. Mol Cell Biol 15, 4291-302 (1995). 32. Fasullo, M., Koudelik, J., AhChing, P., Giallanza, P. & Cera, C. Radiosensitive and mitotic recombination phenotypes of the Saccharomyces cerevisiae dun1 mutant defective in DNA damage-inducible gene expression. Genetics 152, 909- 19 (1999). 33. Kowalski, S. & Laskowski, W. The effect of three rad genes on survival, inter- and intragenic mitotic recombination in Saccharomyces. I. UV irradiation without photoreactivation or liquid-holding post-treatment. Mol Gen Genet 136, 75-86 (1975). 34. Ben-Aroya, S., Koren, A., Liefshitz, B., Steinlauf, R. & Kupiec, M. ELG1, a yeast gene required for genome stability, forms a complex related to replication factor C. Proc Natl Acad Sci U S A 100, 9906-11 (2003). 35. Banerjee, S. & Myung, K. Increased genome instability and telomere length in the elg1-deficient Saccharomyces cerevisiae mutant are regulated by S-phase checkpoints. Eukaryot Cell 3, 1557-66 (2004). 36. Kanellis, P., Agyei, R. & Durocher, D. Elg1 forms an alternative PCNA- interacting RFC complex required to maintain genome stability. Curr Biol 13, 1583-95 (2003). 37. Smith, S. et al. Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 101, 9039-44 (2004). 38. Xu, H., Boone, C. & Klein, H.L. Mrc1 is required for sister chromatid cohesion to aid in recombination repair of spontaneous damage. Mol Cell Biol 24, 7082- 90 (2004). 39. Ajimura, M., Leem, S.H. & Ogawa, H. Identification of new genes required for meiotic recombination in Saccharomyces cerevisiae. Genetics 133, 51-66 (1993). 40. Malone, R.E., Ward, T., Lin, S. & Waring, J. The RAD50 gene, a member of the double strand break repair epistasis group, is not required for spontaneous mitotic recombination in yeast. Curr Genet 18, 111-6 (1990). 41. Xu, X. et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3, 389-95 (1999). 42. Tutt, A.N., van Oostrom, C.T., Ross, G.M., van Steeg, H. & Ashworth, A. Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation. EMBO Rep 3, 255-60 (2002). 43. Xia, F. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci U S A 98, 8644-9 (2001). 44. Yu, V.P. et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous following BRCA2 inactivation. Genes Dev 14, 1400-6 (2000). 45. Bogliolo, M. et al. Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability. Embo J 26, 1340-51 (2007). 46. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922-7 (2002). 47. Rong, L., Palladino, F., Aguilera, A. & Klein, H.L. The hyper-gene conversion hpr5-1 mutation of Saccharomyces cerevisiae is an allele of the SRS2/RADH gene. Genetics 127, 75-85 (1991). 48. Gangloff, S., McDonald, J.P., Bendixen, C., Arthur, L. & Rothstein, R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Mol Cell Biol 14, 8391-8 (1994). 49. Myung, K., Datta, A., Chen, C. & Kolodner, R.D. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nat Genet 27, 113-6 (2001). 50. Watt, P.M., Hickson, I.D., Borts, R.H. & Louis, E.J. SGS1, a homologue of the Bloom's and Werner's syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae. Genetics 144, 935-45 (1996). 51. Schmidt, K.H., Wu, J. & Kolodner, R.D. Control of translocations between highly diverged genes by Sgs1, the Saccharomyces cerevisiae homolog of the Bloom's syndrome protein. Mol Cell Biol 26, 5406-20 (2006). 52. Yamagata, K. et al. Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: implication for genomic instability in human diseases. Proc Natl Acad Sci U S A 95, 8733-8 (1998). 53. Fukuchi, K., Martin, G.M. & Monnat, R.J., Jr. Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc Natl Acad Sci U S A 86, 5893-7 (1989). 54. Fukuchi, K. et al. Elevated spontaneous mutation rate in SV40-transformed Werner syndrome fibroblast cell lines. Somat Cell Mol Genet 11, 303-8 (1985). 55. Liefshitz, B., Steinlauf, R., Friedl, A., Eckardt-Schupp, F. & Kupiec, M. Genetic interactions between mutants of the 'error-prone' repair group of Saccharomyces cerevisiae and their effect on recombination and mutagenesis. Mutat Res 407, 135-45 (1998). 56. Boram, W.R. & Roman, H. Recombination in Saccharomyces cerevisiae: a DNA repair mutation associated with elevated mitotic gene conversion. Proc Natl Acad Sci U S A 73, 2828-32 (1976). 57. Mayer, V.W. & Goin, C.J. Semidominance of rad18-2 for several phenotypic characters in Saccharomyces cerevisiae. Genetics 106, 577-89 (1984). 58. Huang, M.E. & Kolodner, R.D. A biological network in Saccharomyces cerevisiae prevents the deleterious effects of endogenous oxidative DNA damage. Mol Cell 17, 709-20 (2005). 59. Thyagarajan, B., Johnson, B.L. & Campbell, C. The effect of target site transcription on gene targeting in human cells in vitro. Nucleic Acids Res 23, 2784-90 (1995). 60. Chavez, S. et al. A protein complex containing Tho2, Hpr1, Mft1 and a novel protein, Thp2, connects transcription elongation with mitotic recombination in Saccharomyces cerevisiae. Embo J 19, 5824-34 (2000). 61. Aguilera, A. & Klein, H.L. HPR1, a novel yeast gene that prevents intrachromosomal excision recombination, shows carboxy-terminal to the Saccharomyces cerevisiae TOP1 gene. Mol Cell Biol 10, 1439-51 (1990). 62. Prado, F., Piruat, J.I. & Aguilera, A. Recombination between DNA repeats in yeast hpr1delta cells is linked to transcription elongation. Embo J 16, 2826-35 (1997). 63. Fan, H.Y., Merker, R.J. & Klein, H.L. High-copy-number expression of Sub2p, a member of the RNA helicase superfamily, suppresses hpr1-mediated genomic instability. Mol Cell Biol 21, 5459-70 (2001). 64. Jimeno, S., Rondon, A.G., Luna, R. & Aguilera, A. The yeast THO complex and mRNA export factors link RNA metabolism with transcription and genome instability. Embo J 21, 3526-35 (2002). 65. Li, X. & Manley, J.L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365-78 (2005). 66. Gallardo, M. & Aguilera, A. A new hyperrecombination mutation identifies a novel yeast gene, THP1, connecting transcription elongation with mitotic recombination. Genetics 157, 79-89 (2001). 67. Gallardo, M., Luna, R., Erdjument-Bromage, H., Tempst, P. & Aguilera, A. Nab2p and the Thp1p-Sac3p complex functionally interact at the interface between transcription and mRNA metabolism. J Biol Chem 278, 24225-32 (2003). 68. Luna, R. et al. Interdependence between transcription and mRNP processing and export, and its impact on genetic stability. Mol Cell 18, 711-22 (2005). 69. De Piccoli, G. et al. Smc5-Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination. Nat Cell Biol 8, 1032-4 (2006). 70. Lengronne, A. & Schwob, E. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1). Mol Cell 9, 1067-78 (2002).