Table 1. a Selection of Eukaryotic Genes with a Role in the Maintenance of Genome Integrity

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Table 1. a Selection of Eukaryotic Genes with a Role in the Maintenance of Genome Integrity Table 1. A selection of eukaryotic genes 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 1, 2 ASF1 ASF1A Chromatin assembly high high 3 TOP1 TOP1 Topoisomerase I high 3 TOP2 TOP2 Topoisomerase II high Replicative helicase 4, 5 MCM4 MCM4 yes high subunit Origin Replication 6 ORC3/5 ORC3/6L high complex 7 CDC6 CDC6 Replication Initiation high 7, 8 CDC9 LIG1 Ligase I high 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 34 CTF18 CHTF18 RFC-like, Cohesion high 34-37 ELG1 unknown RFC-like high high 11, 38 DDC2 ATRIP Signalling high high 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, 20, RAD50 RAD50 HR and NHEJ high high 28, 40 20 RAD52 RAD52 HR high 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 14 DNL4 LIG4 NHEJ Lig4 syndrome high Chromatin 45, 46 H2A H2AX high decondensation 8, 13, SRS2 FBH1 HR normal high 26, 47 48, 49 TOP3 TOP3A,B HR high high 28, SGS1 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 65 ASF2/SF2 pre-mRNA splicing high 66, 67 THP1-SAC3 SACD1 mRNA export high 68 RRP6 EXOSC10 Nuclear Exosome high 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 7, 8 CDC13 CCNB1 Telomere capping high Cell cycle phosphatase, 7, 8 CDC14 CDC14B high mitotic exit 58 YCS4 NCAPD2 Mitotic condensation high 69 SMC5-SMC6 SMC5-SMC6 Cohesion-related/repair high 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. Saccharomyces cerevisiae 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 topoisomerases 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 protein 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 chromosome instability and mammary adenocarcinomas in mice. Nat Genet 39, 93-8 (2007). 6. Huang, D. & Koshland, D. 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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 gene 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. 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