Defects in the GINS complex increase the instability of repetitive sequences via a recombination-dependent mechanism

English version

Autoři: Malgorzata Jedrychowska ^aff001; Milena Denkiewicz-Kruk ^aff001; Malgorzata Alabrudzinska ^aff001; Adrianna Skoneczna ^aff001; Piotr Jonczyk ^aff001; Michal Dmowski ^aff001; Iwona J. Fijalkowska ^aff001
Působiště autorů: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland ^aff001
Vyšlo v časopise: Defects in the GINS complex increase the instability of repetitive sequences via a recombination-dependent mechanism. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008494
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1008494

Souhrn

Faithful replication and repair of DNA lesions ensure genome maintenance. During replication in eukaryotic cells, DNA is unwound by the CMG helicase complex, which is composed of three major components: the Cdc45 protein, Mcm2-7, and the GINS complex. The CMG in complex with DNA polymerase epsilon (CMG-E) participates in the establishment and progression of the replisome. Impaired functioning of the CMG-E was shown to induce genomic instability and promote the development of various diseases. Therefore, CMG-E components play important roles as caretakers of the genome. In Saccharomyces cerevisiae, the GINS complex is composed of the Psf1, Psf2, Psf3, and Sld5 essential subunits. The Psf1-1 mutant form fails to interact with Psf3, resulting in impaired replisome assembly and chromosome replication. Here, we show increased instability of repeat tracts (mononucleotide, dinucleotide, trinucleotide and longer) in yeast psf1-1 mutants. To identify the mechanisms underlying this effect, we analyzed repeated sequence instability using derivatives of psf1-1 strains lacking genes involved in translesion synthesis, recombination, or mismatch repair. Among these derivatives, deletion of RAD52, RAD51, MMS2, POL32, or PIF1 significantly decreased DNA repeat instability. These results, together with the observed increased amounts of single-stranded DNA regions and Rfa1 foci suggest that recombinational mechanisms make important contributions to repeat tract instability in psf1-1 cells. We propose that defective functioning of the CMG-E complex in psf1-1 cells impairs the progression of DNA replication what increases the contribution of repair mechanisms such as template switch and break-induced replication. These processes require sequence homology search which in case of a repeated DNA tract may result in misalignment leading to its expansion or contraction.

Klíčová slova:

DNA replication – Yeast – Genetic networks – Mutagenesis – DNA repair – Repeated sequences – DNA recombination – Protein structure networks

Zdroje

1. Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. American Association for Cancer Research; 1991;51: 3075–9. Available: http://www.ncbi.nlm.nih.gov/pubmed/2039987

2. Drake JW, Charlesworth B, Charlesworth D, Crow JF. Rates of spontaneous mutation. Genetics. 1998;148: 1667–86. Available: http://www.ncbi.nlm.nih.gov/pubmed/9560386 9560386

3. De Bont R, van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 2004;19: 169–85. Available: http://www.ncbi.nlm.nih.gov/pubmed/15123782 doi: 10.1093/mutage/geh025 15123782

4. Tóth G, Gáspári Z, Jurka J. Microsatellites in different eukaryotic genomes: survey and analysis. Genome Res. Cold Spring Harbor Laboratory Press; 2000;10: 967–81. Available: http://www.ncbi.nlm.nih.gov/pubmed/10899146 doi: 10.1101/gr.10.7.967 10899146

5. Ramel C. Mini- and microsatellites. Environ Health Perspect. 1997;105: 781–789. doi: 10.1289/ehp.97105s4781 9255562

6. Wang Z, Weber JL, Zhong G, Tanksley SD. Survey of plant short tandem DNA repeats. Theor Appl Genet. 1994;88: 1–6. doi: 10.1007/BF00222386 24185874

7. Schug MD, Wetterstrand KA, Gaudette MS, Lim RH, Hutter CM, Aquadro CF. The distribution and frequency of microsatellite loci in Drosophila melanogaster. Mol Ecol. John Wiley & Sons, Ltd (10.1111); 1998;7: 57–70. doi: 10.1046/j.1365-294x.1998.00304.x 9465417

8. Wren JD, Forgacs E, Fondon JW, Pertsemlidis A, Cheng SY, Gallardo T, et al. Repeat Polymorphisms within Gene Regions: Phenotypic and Evolutionary Implications. Am J Hum Genet. Cell Press; 2000;67: 345–356. doi: 10.1086/303013 10889045

9. Lafreniére RG, Rochefort DL, Chrétien N, Rommens JM, Cochius JI, Kälviäinen R, et al. Unstable insertion in the 5′ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nat Genet. Nature Publishing Group; 1997;15: 298–302. doi: 10.1038/ng0397-298 9054946

10. Kennedy GC, German MS, Rutter WJ. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet. Nature Publishing Group; 1995;9: 293–298. doi: 10.1038/ng0395-293 7773292

11. Yang B, Chan RCK, Jing J, Li T, Sham P, Chen RYL. A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention deficit hyperactivity disorder. Am J Med Genet Part B Neuropsychiatr Genet. John Wiley & Sons, Ltd; 2007;144B: 541–550. doi: 10.1002/ajmg.b.30453 17440978

12. Kirkbride HJ, Bolscher JG, Nazmi K, Vinall LE, Nash MW, Moss FM, et al. Genetic polymorphism of MUC7: Allele frequencies and association with asthma. Eur J Hum Genet. Nature Publishing Group; 2001;9: 347–354. doi: 10.1038/sj.ejhg.5200642 11378823

13. Kyo K, Parkes M, Takei Y, Nishimori H, Vyas P, Satsangi J, et al. Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3. Hum Mol Genet. 1999;8: 307–11. Available: http://www.ncbi.nlm.nih.gov/pubmed/9931338 doi: 10.1093/hmg/8.2.307 9931338

14. Jeong YH, Kim MC, Ahn E-K, Seol S-Y, Do E-J, Choi H-J, et al. Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma. von Elm E, editor. PLoS One. Public Library of Science; 2007;2: e1163. doi: 10.1371/journal.pone.0001163 18000536

15. Krontiris TG, Devlin B, Karp DD, Robert NJ, Risch N. An Association between the Risk of Cancer and Mutations in the HRAS1 Minisatellite Locus. N Engl J Med. Massachusetts Medical Society; 1993;329: 517–523. doi: 10.1056/NEJM199308193290801 8336750

16. Wang L, Ogawa S, Hangaishi A, Qiao Y, Hosoya N, Nanya Y, et al. Molecular characterization of the recurrent unbalanced translocation der(1;7)(q10;p10). Blood. American Society of Hematology; 2003;102: 2597–604. doi: 10.1182/blood-2003-01-0031 12816870

17. Mirkin SM. Expandable DNA repeats and human disease. Nature. 2007;447: 932–940. doi: 10.1038/nature05977 17581576

18. Pearson CE, Edamura KN, Cleary JD. Repeat instability: Mechanisms of dynamic mutations. Nat Rev Genet. 2005;6: 729–742. doi: 10.1038/nrg1689 16205713

19. Zhao XN, Usdin K. The Repeat Expansion Diseases: The dark side of DNA repair. DNA Repair (Amst). Elsevier B.V.; 2015;32: 96–105. doi: 10.1016/j.dnarep.2015.04.019 26002199

20. Fan H, Chu JY. A Brief Review of Short Tandem Repeat Mutation. Genomics, Proteomics Bioinforma. Beijing Institute of Genomics; 2007;5: 7–14. doi: 10.1016/S1672-0229(07)60009-6 17572359

21. Garrido-Ramos MA. Satellite DNA: An evolving topic. Genes (Basel). 2017;8. doi: 10.3390/genes8090230 28926993

22. Tachida H, Iizuka M. Persistence of repeated sequences that evolve by replication slippage. Genetics. 1992;131.

23. Cleary JD, Pearson CE. Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability. Trends Genet. Elsevier Current Trends; 2005;21: 272–280. doi: 10.1016/j.tig.2005.03.008 15851063

24. Mirkin SM. DNA structures, repeat expansions and human hereditary disorders. Curr Opin Struct Biol. Elsevier Current Trends; 2006;16: 351–358. doi: 10.1016/j.sbi.2006.05.004 16713248

25. Harding RM, Boyce AJ, Clegg JB. The evolution of tandemly repetitive DNA: recombination rules. Genetics. Genetics Society of America; 1992;132: 847–59. Available: http://www.ncbi.nlm.nih.gov/pubmed/1468634 1468634

26. Wells RD, Dere R, Hebert ML, Napierala M, Son LS. Advances in mechanisms of genetic instability related to hereditary neurological diseases. Nucleic Acids Res. Narnia; 2005;33: 3785–3798. doi: 10.1093/nar/gki697 16006624

27. Polleys EJ, House NCM, Freudenreich CH. Role of recombination and replication fork restart in repeat instability. DNA Repair (Amst). Elsevier; 2017;56: 156–165. doi: 10.1016/j.dnarep.2017.06.018 28641941

28. Jaworski A, Rosche WA, Gellibolian R, Kang S, Shimizu M, Bowater RP, et al. Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases. Proc Natl Acad Sci U S A. National Academy of Sciences; 1995;92: 11019–23. doi: 10.1073/pnas.92.24.11019 7479928

29. Panigrahi GB, Lau R, Montgomery SE, Leonard MR, Pearson CE. Slipped (CTG)•(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair. Nat Struct Mol Biol. Nature Publishing Group; 2005;12: 654–662. doi: 10.1038/nsmb959 16025129

30. Daee DL, Mertz T, Lahue RS. Postreplication Repair Inhibits CAG · CTG Repeat Expansions in Saccharomyces cerevisiae. Mol Cell Biol. 2007;27: 102–110. doi: 10.1128/MCB.01167-06 17060452

31. Kovtun I V., Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature. Nature Publishing Group; 2007;447: 447–452. doi: 10.1038/nature05778 17450122

32. McMurray CT. Hijacking of the mismatch repair system to cause CAG expansion and cell death in neurodegenerative disease. DNA Repair (Amst). NIH Public Access; 2008;7: 1121–34. doi: 10.1016/j.dnarep.2008.03.013 18472310

33. McMurray CT. Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet. NIH Public Access; 2010;11: 786–99. doi: 10.1038/nrg2828 20953213

34. Usdin K, House NCM, Freudenreich CH. Repeat instability during DNA repair: Insights from model systems. Crit Rev Biochem Mol Biol. Informa Healthcare; 2015;50: 142–167. doi: 10.3109/10409238.2014.999192 25608779

35. Dion V, Wilson JH. Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet. Elsevier Current Trends; 2009;25: 288–297. doi: 10.1016/j.tig.2009.04.007 19540013

36. Wierdl M, Greene CN, Datta A, Jinks-Robertson S, Petes TD. Destabilization of Simple Repetitive DNA Sequences by Transcription in Yeast. Genetics. 1996;143.

37. Brohede J, Ellegren H. Microsatellite evolution: polarity of substitutions within repeats and neutrality of flanking sequences. Proc R Soc London Ser B Biol Sci. 1999;266: 825–833. doi: 10.1098/rspb.1999.0712 10343406

38. Gendrel CG, Boulet A, Dutreix M. (CA/GT)(n) microsatellites affect homologous recombination during yeast meiosis. Genes Dev. Cold Spring Harbor Laboratory Press; 2000;14: 1261–8. Available: http://www.ncbi.nlm.nih.gov/pubmed/10817760

39. Li Y, Fahima T, Korol AB, Peng J, R MS, Kirzhner V, et al. Microsatellite Diversity Correlated with Ecological-Edaphic and Genetic Factors in Three Microsites of Wild Emmer Wheat in North Israel. Mol Biol Evol. 2000;17: 851–862. doi: 10.1093/oxfordjournals.molbev.a026365 10833191

40. Li Y-C, Fahima T, Röder MS, Kirzhner VM, Beiles A, Korol AB, et al. Genetic effects on microsatellite diversity in wild emmer wheat (Triticum dicoccoides) at the Yehudiyya microsite, Israel. Heredity (Edinb). Nature Publishing Group; 2003;90: 150–156. doi: 10.1038/sj.hdy.6800190 12634821

41. Lenzmeier BA, Freudenreich CH. Trinucleotide repeat instability: a hairpin curve at the crossroads of replication, recombination, and repair. Cytogenet Genome Res. Karger Publishers; 2003;100: 7–24. doi: 10.1159/000072836 14526162

42. Iraqui I, Chekkal Y, Jmari N, Pietrobon V, Fréon K, Costes A, et al. Recovery of Arrested Replication Forks by Homologous Recombination Is Error-Prone. PLoS Genet. 2012;8. doi: 10.1371/journal.pgen.1002976 23093942

43. Kokoska RJ, Stefanovic L, DeMai J, Petes TD. Increased rates of genomic deletions generated by mutations in the yeast gene encoding DNA polymerase delta or by decreases in the cellular levels of DNA polymerase delta. Mol Cell Biol. 2000;20: 7490–504. doi: 10.1128/mcb.20.20.7490-7504.2000 11003646

44. Shah KA, Shishkin AA, Voineagu I, Pavlov YI, Shcherbakova P V., Mirkin SM. Role of DNA Polymerases in Repeat-Mediated Genome Instability. Cell Rep. The Authors; 2012;2: 1088–1095. doi: 10.1016/j.celrep.2012.10.006 23142667

45. Tran HT, Gordenin DA, Resnick MA. The 3’—>5’ exonucleases of DNA polymerases delta and epsilon and the 5’—>3’ exonuclease Exo1 have major roles in postreplication mutation avoidance in Saccharomyces cerevisiae. Mol Cell Biol. 1999;19: 2000–7. doi: 10.1128/mcb.19.3.2000 10022887

46. Schweitzer JK, Livingston DM. The effect of DNA replication mutations on CAG tract stability in yeast. Genetics. 1999;152: 953–963. doi: 10.1534/genetics.112.541.test 10388815

47. Zheng DQ, Petes TD. Genome instability induced by low levels of replicative DNA polymerases in yeast. Genes (Basel). 2018;9. doi: 10.3390/genes9110539 30405078

48. Kokoska RJ, Stefanovic L, Tran HT, Resnick M a, Gordenin D a, Petes TD. Destabilization of yeast micro- and minisatellite DNA sequences by mutations affecting a nuclease involved in Okazaki fragment processing (rad27) and DNA polymerase delta (pol3-t). Mol Cell Biol. 1998;18: 2779–2788. doi: 10.1128/mcb.18.5.2779 9566897

49. Kokoska RJ, Stefanovic L, Buermeyer AB, Liskay RM, Petes TD. A Mutation of the Yeast Gene Encoding PCNA Destabilizes Both Microsatellite and Minisatellite DNA Sequences. Genetics. 1999;151.

50. Kurth I, O’Donnell M. New insights into replisome fluidity during chromosome replication. Trends Biochem Sci. Elsevier Ltd; 2013;38: 195–203. doi: 10.1016/j.tibs.2012.10.003 23153958

51. Onesti S, MacNeill SA. Structure and evolutionary origins of the CMG complex. Chromosoma. Springer-Verlag; 2013;122: 47–53. doi: 10.1007/s00412-013-0397-x 23412083

52. Kanemaki M, Sanchez-Diaz A, Gambus A, Labib K. Functional proteomic identification of DNA replication proteins by induced proteolysis in vivo. Nature. 2003;423: 720–725. doi: 10.1038/nature01692 12768207

53. Kubota Y, Takase Y, Komori Y, Hashimoto Y, Arata T, Kamimura Y, et al. A novel ring-like complex of Xenopus proteins essential for the initiation of DNA replication. Genes Dev. 2003;17: 1141–1152. doi: 10.1101/gad.1070003 12730133

54. Takayama Y, Kamimura Y, Okawa M, Muramatsu S, Sugino A, Araki H. GINS, a novel multiprotein complex required for chromosomal DNA replication in budding yeast. Genes Dev. 2003;17: 1153–1165. doi: 10.1101/gad.1065903 12730134

55. Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F, Edmondson RD, et al. GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol. 2006;8: 358–366. doi: 10.1038/ncb1382 16531994

56. Langston LD, Mayle R, Schauer GD, Yurieva O, Zhang D, Yao NY, et al. Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks. Elife. 2017;6. doi: 10.7554/elife.29118 28869037

57. Langston LD, Zhang D, Yurieva O, Georgescu RE, Finkelstein J, Yao NY, et al. CMG helicase and DNA polymerase ε form a functional 15-subunit holoenzyme for eukaryotic leading-strand DNA replication. Proc Natl Acad Sci. 2014;111: 15390–15395. doi: 10.1073/pnas.1418334111 25313033

58. Bermudez VP, Farina A, Raghavan V, Tappin I, Hurwitz J. Studies on human DNA polymerase epsilon and GINS complex and their role in DNA replication. J Biol Chem. 2011;286: 28963–77. doi: 10.1074/jbc.M111.256289 21705323

59. Handa T, Kanke M, Takahashi TS, Nakagawa T, Masukata H. DNA polymerization-independent functions of DNA polymerase epsilon in assembly and progression of the replisome in fission yeast. Mol Biol Cell. 2012;23: 3240–3253. doi: 10.1091/mbc.E12-05-0339 22718908

60. Cottineau J, Kottemann MC, Lach FP, Kang YH, Vély F, Deenick EK, et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest. 2017;127: 1991–2006. doi: 10.1172/JCI90727 28414293

61. Sengupta S, van Deursen F, de Piccoli G, Labib K. Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome. Curr Biol. Elsevier Ltd; 2013;23: 543–552. doi: 10.1016/j.cub.2013.02.011 23499531

62. Grabowska E, Wronska U, Denkiewicz M, Jaszczur M, Respondek A, Alabrudzinska M, et al. Proper functioning of the GINS complex is important for the fidelity of DNA replication in yeast. Mol Microbiol. 2014;92: 659–680. doi: 10.1111/mmi.12580 24628792

63. Costa A, Renault L, Swuec P, Petojevic T, Pesavento JJ, Ilves I, et al. DNA binding polarity, dimerization, and ATPase ring remodeling in the CMG helicase of the eukaryotic replisome. Elife. 2014;3: e03273. doi: 10.7554/eLife.03273 25117490

64. Yuan Z, Bai L, Sun J, Georgescu R, Liu J, O’Donnell ME, et al. Structure of the eukaryotic replicative CMG helicase suggests a pumpjack motion for translocation. Nat Struct Mol Biol. Nature Publishing Group; 2016;23: 217–24. doi: 10.1038/nsmb.3170 26854665

65. Miret JJ, Pessoa-Brandão L, Lahue RS. Orientation-dependent and sequence-specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1998;95: 12438–43. doi: 10.1073/pnas.95.21.12438 9770504

66. Henderson ST, Petes TD. Instability of simple sequence DNA in Saccharomyces cerevisiae. Mol Cell Biol. 1992;12: 2749–2757. doi: 10.1128/mcb.12.6.2749 1588966

67. Sia EA, Kokoska RJ, Dominska M, Greenwell P, Petes TD. Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Mol Cell Biol. 1997;17: 2851–8. doi: 10.1128/mcb.17.5.2851 9111357

68. Mosbach V, Poggi L, Richard G-F. Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy. Curr Genet. Springer Berlin Heidelberg; 2018;0: 0. doi: 10.1007/s00294-018-0865-1 29974202

69. Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012;122: 821–832. doi: 10.1172/JCI61014 22354167

70. Hughes CR, Guasti L, Meimaridou E, Chuang C, Schimenti JC, King PJ, et al. MCM4 mutation causes adrenal failure, Short Stature, and Natural Killer Cell Deficiency in Humans. J Clin Invest. 2012;122: 814–820. doi: 10.1172/JCI60224 22354170

71. Seo Y-S, Kang Y-H. The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy. Front Mol Biosci. Frontiers; 2018;5: 26. doi: 10.3389/fmolb.2018.00026 29651420

72. Boeke JD, LaCroute F, Fink GR. A positive selection for mutants lacking 5’ phosphate decarboxylase activity in yeast: 5 fluoro-orotic acid resistance. Mol Gen Genet. 1984;197: 345–346. doi: 10.1007/bf00330984 6394957

73. Rolfsmeier ML, Dixon MJ, Pessoa-Brandão L, Pelletier R, Miret JJ, Lahue RS. Cis-elements governing trinucleotide repeat instability in Saccharomyces cerevisiae. Genetics. 2001;157: 1569–1579. 11290713

74. Richards RI, Sutherland GR. Simple repeat DNA is not replicated simply. Nat Genet. 1994;6: 114–116. doi: 10.1038/ng0294-114 8162063

75. Eckert KA, Hile SE. Every microsatellite is different: Intrinsic DNA features dictate mutagenesis of common microsatellites present in the human genome. Mol Carcinog. John Wiley & Sons, Ltd; 2009;48: 379–388. doi: 10.1002/mc.20499 19306292

76. Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev. Elsevier Current Trends; 1999;9: 89–96. doi: 10.1016/s0959-437x(99)80013-6 10072354

77. Liu D, Keijzers G, Rasmussen LJ. DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res Mutat Res. Elsevier; 2017;773: 174–187. doi: 10.1016/J.MRREV.2017.07.001 28927527

78. Johnson RE, Kovvali GK, Prakash L, Prakash S. Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. J Biol Chem. American Society for Biochemistry and Molecular Biology; 1996;271: 7285–8. doi: 10.1074/jbc.271.13.7285 8631743

79. Marsischky GT, Filosi N, Kane MF, Kolodner R. Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes Dev. 1996;10: 407–20. Available: http://www.ncbi.nlm.nih.gov/pubmed/8600025 doi: 10.1101/gad.10.4.407 8600025

80. Bishop DK, Williamson MS, Fogel S, Kolodner RD. The role of heteroduplex correction in gene conversion in Saccharomyces cerevisiae. Nature. Nature Publishing Group; 1987;328: 362–364. doi: 10.1038/328362a0 3299108

81. Tran HT, Gordenin DA, Resnick MA. The prevention of repeat-associated deletions in Saccharomyces cerevisiae by mismatch repair depends on size and origin of deletions. Genetics. 1996. pp. 1579–1587. 8844147

82. Sia EA, Jinks-Robertson S, Petes TD. Genetic control of microsatellite stability. Mutat Res Repair. Elsevier; 1997;383: 61–70. doi: 10.1016/S0921-8777(96)00046-8

83. Greene CN, Jinks-Robertson S. Frameshift intermediates in homopolymer runs are removed efficiently by yeast mismatch repair proteins. Mol Cell Biol. American Society for Microbiology Journals; 1997;17: 2844–50. doi: 10.1128/mcb.17.5.2844 9111356

84. Greene CN, Jinks-Robertson S. Spontaneous frameshift mutations in saccharomyces cerevisiae: Accumulation during dna replication and removal by proofreading and mismatch repair activities. Genetics. 2001;159: 65–75. 11560887

85. Heale SM, Petes TD. The stabilization of repetitive tracts of DNA by variant repeats requires a functional DNA mismatch repair system. Cell. Cell Press; 1995;83: 539–545. doi: 10.1016/0092-8674(95)90093-4 7585956

86. Strand M, Earley MC, Crouse GF, Petes TD. Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. National Academy of Sciences; 1995;92: 10418–21. doi: 10.1073/pnas.92.22.10418 7479796

87. Sia EA, Dominska M, Stefanovic L, Petes TD. Isolation and Characterization of Point Mutations in Mismatch Repair Genes That Destabilize Microsatellites in Yeast. Mol Cell Biol. American Society for Microbiology Journals; 2001;21: 8157–8167. doi: 10.1128/MCB.21.23.8157-8167.2001 11689704

88. Makarova A V, Stodola JL, Burgers PM. A four-subunit DNA polymerase ζ complex containing Pol δ accessory subunits is essential for PCNA-mediated mutagenesis. Nucleic Acids Res. 2012;40: 11618–26. doi: 10.1093/nar/gks948 23066099

89. Johnson RE, Prakash L, Prakash S. Pol31 and Pol32 subunits of yeast DNA polymerase δ are also essential subunits of DNA polymerase ζ. Proc Natl Acad Sci U S A. 2012;109: 12455–60. doi: 10.1073/pnas.1206052109 22711820

90. Pâques F, Haber JE. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1999;63: 349–404. Available: http://www.ncbi.nlm.nih.gov/pubmed/10357855 10357855

91. Symington LS, Rothstein R, Lisby M. Mechanisms and regulation of mitotic recombination in saccharomyces cerevisiae. Genetics. 2014;198: 795–835. doi: 10.1534/genetics.114.166140 25381364

92. Hum YF, Jinks-Robertson S. DNA strand-exchange patterns associated with double-strand break-induced and spontaneous mitotic crossovers in Saccharomyces cerevisiae. Copenhaver GP, editor. PLOS Genet. Public Library of Science; 2018;14: e1007302. doi: 10.1371/journal.pgen.1007302 29579095

93. Krol K, Antoniuk-Majchrzak J, Skoneczny M, Sienko M, Jendrysek J, Rumienczyk I, et al. Lack of G1/S control destabilizes the yeast genome via replication stress-induced DSBs and illegitimate recombination. J Cell Sci. The Company of Biologists Ltd; 2018;131: jcs226480. doi: 10.1242/jcs.226480 30463853

94. Skoneczna A, Krol K, Skoneczny M. How Do Yeast and Other Fungi Recognize and Respond to Genome Perturbations? Stress Response Mechanisms in Fungi. 2018. doi: 10.1007/978-3-030-00683-9_3

95. Piazza A, Heyer WD. Homologous Recombination and the Formation of Complex Genomic Rearrangements. Trends Cell Biol. Elsevier Ltd; 2019;29: 135–149. doi: 10.1016/j.tcb.2018.10.006 30497856

96. Godin SK, Sullivan MR, Bernstein KA. Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication. Biochem Cell Biol. NIH Public Access; 2016;94: 407–418. doi: 10.1139/bcb-2016-0012 27224545

97. Bhat KP, Cortez D. RPA and RAD51: fork reversal, fork protection, and genome stability. Nat Struct Mol Biol. Nature Publishing Group; 2018;25: 446–453. doi: 10.1038/s41594-018-0075-z 29807999

98. Andriuskevicius T, Kotenko O, Makovets S. Putting together and taking apart: assembly and disassembly of the Rad51 nucleoprotein filament in DNA repair and genome stability. Cell Stress. Shared Science Publishers; 2018;2: 96–112. doi: 10.15698/cst2018.05.134 31225474

99. Jenkins SS, Gore S, Guo X, Liu J, Ede C, Veaute X, et al. Role of the Srs2-Rad51 Interaction Domain in Crossover Control in Saccharomyces cerevisiae. Genetics. Genetics; 2019; genetics.302337.2019. doi: 10.1534/genetics.119.302337 31142613

100. Karras GI, Jentsch S. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase. Cell. Elsevier Ltd; 2010;141: 255–67. doi: 10.1016/j.cell.2010.02.028 20403322

101. Vanoli F, Fumasoni M, Szakal B, Maloisel L, Branzei D. Replication and Recombination Factors Contributing to Recombination-Dependent Bypass of DNA Lesions by Template Switch. Haber JE, editor. PLoS Genet. Public Library of Science; 2010;6: e1001205. doi: 10.1371/journal.pgen.1001205 21085632

102. Branzei D, Szakal B. Building up and breaking down: mechanisms controlling recombination during replication. Crit Rev Biochem Mol Biol. 2017;52: 381–394. doi: 10.1080/10409238.2017.1304355 28325102

103. Boiteux S, Jinks-Robertson S, Hartwell LH, Crouse GF. DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae. Genetics. Genetics; 2013;193: 1025–64. doi: 10.1534/genetics.112.145219 23547164

104. Saugar I, Ortiz-Bazán MÁ, Tercero JA. Tolerating DNA damage during eukaryotic chromosome replication. Exp Cell Res. Academic Press; 2014;329: 170–177. doi: 10.1016/j.yexcr.2014.07.009 25038291

105. Kramara J, Osia B, Malkova A. Break-Induced Replication: The Where, The Why, and The How. Trends Genet. Elsevier Current Trends; 2018;34: 518–531. doi: 10.1016/j.tig.2018.04.002 29735283

106. Leffak M. Break-induced replication links microsatellite expansion to complex genome rearrangements. BioEssays. 2017;39: 1–8. doi: 10.1002/bies.201700025 28621832

107. Lydeard JR, Lipkin-Moore Z, Sheu YJ, Stillman B, Burgers PM, Haber JE. Break-induced replication requires all essential DNA replication factors except those specific for pre-RC assembly. Genes Dev. 2010;24: 1133–1144. doi: 10.1101/gad.1922610 20516198

108. Wilson MA, Kwon Y, Xu Y, Chung WH, Chi P, Niu H, et al. Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration. Nature. Nature Publishing Group; 2013;502: 393–396. doi: 10.1038/nature12585 24025768

109. Donnianni RA, Symington LS. Break-induced replication occurs by conservative DNA synthesis. Proc Natl Acad Sci. 2013;110: 13475–13480. doi: 10.1073/pnas.1309800110 23898170

110. Lydeard JR, Jain S, Yamaguchi M, Haber JE. Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature. 2007;448: 820–823. doi: 10.1038/nature06047 17671506

111. Gerik KJ, Gerik KJ, Pautz A, Pautz A. Characterization of the Two Small Subunits of Saccharomyces cerevisiae DNA Polymerase δ. Mol Biol. 1998;273: 19747–19755. doi: 10.1074/jbc.273.31.19747 9677405

112. Szwajczak E, Fijalkowska IJ, Suski C. The CysB motif of Rev3p involved in the formation of the four-subunit DNA polymerase ζ is required for defective-replisome-induced mutagenesis. Mol Microbiol. 2017;106: 659–672. doi: 10.1111/mmi.13846 28941243

113. Huang ME, de Calignon a, Nicolas a, Galibert F. POL32, a subunit of the Saccharomyces cerevisiae DNA polymerase delta, defines a link between DNA replication and the mutagenic bypass repair pathway. Curr Genet. 2000;38: 178–187. doi: 10.1007/s002940000149 11126776

114. Buzovetsky O, Kwon Y, Pham NT, Kim C, Ira G, Sung P, et al. Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication. Cell Rep. ElsevierCompany.; 2017;21: 1707–1714. doi: 10.1016/j.celrep.2017.10.079 29141206

115. Boulé JB, Zakian VA. Roles of Pif1-like helicases in the maintenance of genomic stability. Nucleic Acids Res. 2006;34: 4147–4153. doi: 10.1093/nar/gkl561 16935874

116. Saini N, Ramakrishnan S, Elango R, Ayyar S, Zhang Y, Deem A, et al. Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature. 2013;502: 389–392. doi: 10.1038/nature12584 24025772

117. Van Dyck E, Foury F, Stillman B, Brill SJ. A single-stranded DNA binding protein required for mitochondrial DNA replication in S. cerevisiae is homologous to E. coli SSB. EMBO J. 1992;11: 3421–3430. doi: 10.1002/j.1460-2075.1992.tb05421.x 1324172

118. Foury F, Van Dyck E. A PIF-dependent recombinogenic signal in the mitochondrial DNA of yeast. EMBO J. 1985;4: 3525–3530. doi: 10.1002/j.1460-2075.1985.tb04112.x 16453651

119. Serero A, Jubin C, Loeillet S, Legoix-Né P, Nicolas AG. Mutational landscape of yeast mutator strains. Proc Natl Acad Sci U S A. 2014;111: 1897–902. doi: 10.1073/pnas.1314423111 24449905

120. Rasmussen AK, Chatterjee A, Rasmussen LJ, Singh KK. Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae. Nucleic Acids Res. 2003;31: 3909–3917. doi: 10.1093/nar/gkg446 12853606

121. Zhou JC, Janska A, Goswami P, Renault L, Abid Ali F, Kotecha A, et al. CMG–Pol epsilon dynamics suggests a mechanism for the establishment of leading-strand synthesis in the eukaryotic replisome. Proc Natl Acad Sci. 2017;114: 201700530. doi: 10.1073/pnas.1700530114 28373564

122. Douglas ME, Ali FA, Costa A, Diffley JFX. The mechanism of eukaryotic CMG helicase activation. Nature. Nature Publishing Group; 2018;555: 265–268. doi: 10.1038/nature25787 29489749

123. Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, et al. Friedreich’s Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion. Science (80-). 1996;271: 1423 LP– 1427. doi: 10.1126/science.271.5254.1423 8596916

124. Shishkin AA, Voineagu I, Matera R, Cherng N, Chernet BT, Krasilnikova MM, et al. Large-Scale Expansions of Friedreich’s Ataxia GAA Repeats in Yeast. Mol Cell. Elsevier Inc.; 2009;35: 82–92. doi: 10.1016/j.molcel.2009.06.017 19595718

125. Ohshima K, Kang S, Larson JE, Wells RD. Cloning, characterization, and properties of seven triplet repeat DNA sequences. J Biol Chem. American Society for Biochemistry and Molecular Biology; 1996;271: 16773–83. doi: 10.1074/jbc.271.28.16773 8663377

126. Gacy AM, Goellner GM, Spiro C, Chen X, Gupta G, Bradbury EM, et al. GAA Instability in Friedreich’s Ataxia Shares a Common, DNA-Directed and Intraallelic Mechanism with Other Trinucleotide Diseases. Mol Cell. Cell Press; 1998;1: 583–593. doi: 10.1016/s1097-2765(00)80058-1 9660942

127. Baptiste BA, Ananda G, Strubczewski N, Lutzkanin A, Khoo SJ, Srikanth A, et al. Mature Microsatellites: Mechanisms Underlying Dinucleotide Microsatellite Mutational Biases in Human Cells. G3 Genes, Genomes, Genet. G3: Genes, Genomes, Genetics; 2013;3: 451–463. doi: 10.1534/G3.112.005173 23450065

128. Ohshima K, Montermini L, Wells RD, Pandolfo M. Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J Biol Chem. American Society for Biochemistry and Molecular Biology; 1998;273: 14588–95. doi: 10.1074/jbc.273.23.14588 9603975

129. Krasilnikova MM, Mirkin SM. Replication stalling at Friedreich’s ataxia (GAA)n repeats in vivo. Mol Cell Biol. American Society for Microbiology (ASM); 2004;24: 2286–95. doi: 10.1128/MCB.24.6.2286-2295.2004 14993268

130. Pollard LM, Sharma R, Gómez M, Shah S, Delatycki MB, Pianese L, et al. Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia. Nucleic Acids Res. Oxford University Press; 2004;32: 5962. doi: 10.1093/nar/gkh933 15534367

131. Gadgil R, Barthelemy J, Lewis T, Leffak M. Replication stalling and DNA microsatellite instability. Biophys Chem. Elsevier B.V.; 2017;225: 38–48. doi: 10.1016/j.bpc.2016.11.007 27914716

132. Freudenreich CH, Kantrow SM, Zakian VA. Expansion and length-dependent fragility of CTG repeats in yeast. Science (80-). 1998;279: 853–856. doi: 10.1126/science.279.5352.853 9452383

133. Dixon MJ, Lahue RS. Examining the potential role of DNA polymerases eta and zeta in triplet repeat instability in yeast. DNA Repair (Amst). 2002;1: 763–70. Available: http://www.ncbi.nlm.nih.gov/pubmed/12509280

134. Northam MR, Moore EA, Mertz TM, Binz SK, Stith CM, Stepchenkova EI, et al. DNA polymerases ζ and Rev1 mediate error-prone bypass of non-B DNA structures. Nucleic Acids Res. 2014;42: 290–306. doi: 10.1093/nar/gkt830 24049079

135. Kunkel TA. Frameshift mutagenesis by eucaryotic DNA polymerases in vitro. J Biol Chem. 1986;261: 13581–13587. 3759982

136. Kunkel T a, Bebenek K. DNA replication fidelity. Annu Rev Biochem. 2000;69: 497–529. doi: 10.1146/annurev.biochem.69.1.497 10966467

137. Streisinger G, Okada Y, Emrich J, Newton J, Tsugita A, Terzaghi E, et al. Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday. Cold Spring Harb Symp Quant Biol. 1966;31: 77–84. Available: http://www.ncbi.nlm.nih.gov/pubmed/5237214 doi: 10.1101/sqb.1966.031.01.014 5237214

138. Polyzos AA, McMurray CT. Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts. DNA Repair (Amst). Elsevier; 2017;56: 144–155. doi: 10.1016/j.dnarep.2017.06.017 28690053

139. Kunkel TA, Erie DA. Eukaryotic Mismatch Repair in Relation to DNA Replication. Annu Rev Genet. 2015;49: 291–313. doi: 10.1146/annurev-genet-112414-054722 26436461

140. Strathern JN, Shafer BK, McGill CB. DNA synthesis errors associated with double-strand-break repair. Genetics. Genetics Society of America; 1995;140: 965–72. Available: http://www.ncbi.nlm.nih.gov/pubmed/7672595 7672595

141. Yang Y, Sterling J, Storici F, Resnick MA, Gordenin DA. Hypermutability of Damaged Single-Strand DNA Formed at Double-Strand Breaks and Uncapped Telomeres in Yeast Saccharomyces cerevisiae. Cohen-Fix O, editor. PLoS Genet. Public Library of Science; 2008;4: e1000264. doi: 10.1371/journal.pgen.1000264 19023402

142. Malkova A, Haber JE. Mutations Arising During Repair of Chromosome Breaks. Annu Rev Genet. 2012;46: 455–473. doi: 10.1146/annurev-genet-110711-155547 23146099

143. Gao Y, Mutter-Rottmayer E, Zlatanou A, Vaziri C, Yang Y. Mechanisms of post-replication DNA repair. Genes (Basel). 2017;8. doi: 10.3390/genes8020064 28208741

144. Kalimutho M, Bain AL, Mukherjee B, Nag P, Nanayakkara DM, Harten SK, et al. Enhanced dependency of KRAS-mutant colorectal cancer cells on RAD51-dependent homologous recombination repair identified from genetic interactions in Saccharomyces cerevisiae. Mol Oncol. John Wiley & Sons, Ltd; 2017;11: 470–490. doi: 10.1002/1878-0261.12040 28173629

145. Anand RP, Tsaponina O, Greenwell PW, Lee C-S, Du W, Petes TD, et al. Chromosome rearrangements via template switching between diverged repeated sequences. Genes Dev. Cold Spring Harbor Laboratory Press; 2014;28: 2394–406. doi: 10.1101/gad.250258.114 25367035

146. Halas A, Krawczyk M, Sledziewska-Gojska E. PCNA SUMOylation protects against PCNA polyubiquitination-mediated, Rad59-dependent, spontaneous, intrachromosomal gene conversion. Mutat Res Mol Mech Mutagen. Elsevier; 2016;791–792: 10–18. doi: 10.1016/J.MRFMMM.2016.08.001 27505077

147. Kim JC, Harris ST, Dinter T, Shah KA, Mirkin SM. The role of break-induced replication in large-scale expansions of (CAG)n/(CTG)n repeats. Nat Struct Mol Biol. Nature Publishing Group; 2017;24: 55–60. doi: 10.1038/nsmb.3334 27918542

148. Pel DM van, Stirling PC, Minaker SW, Sipahimalani P, Hieter P. Saccharomyces cerevisiae Genetics Predicts Candidate Therapeutic Genetic Interactions at the Mammalian Replication Fork. G3 Genes, Genomes, Genet. G3: Genes, Genomes, Genetics; 2013;3: 273–282. doi: 10.1534/G3.112.004754 23390603

149. Yeeles JTP, Marians KJ. The Escherichia coli replisome is inherently DNA damage tolerant. Science (80-). 2011;334: 235–238. doi: 10.1126/science.1209111 21998391

150. Heller RC, Marians KJ. Replisome assembly and the direct restart of stalled replication forks. Nat Rev Mol Cell Biol. Nature Publishing Group; 2006;7: 932–943. doi: 10.1038/nrm2058 17139333

151. Fumasoni M, Zwicky K, Vanoli F, Lopes M, Branzei D. Error-Free DNA Damage Tolerance and Sister Chromatid Proximity during DNA Replication Rely on the Polα/Primase/Ctf4 Complex. Mol Cell. Cell Press; 2015;57: 812–823. doi: 10.1016/j.molcel.2014.12.038 25661486

152. Hashimoto Y, Puddu F, Costanzo V. RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat Struct Mol Biol. Nature Publishing Group; 2012;19: 17–24. doi: 10.1038/nsmb.2177 22139015

153. Byun TS, Pacek M, Yee MC, Walter JC, Cimprich K a. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19: 1040–1052. doi: 10.1101/gad.1301205 15833913

154. Hashimoto Y, Ray Chaudhuri A, Lopes M, Costanzo V. Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nat Struct Mol Biol. Europe PMC Funders; 2010;17: 1305–11. doi: 10.1038/nsmb.1927 20935632

155. Branzei D, Psakhye I. DNA damage tolerance. Curr Opin Cell Biol. Elsevier Current Trends; 2016;40: 137–144. doi: 10.1016/j.ceb.2016.03.015 27060551

156. Neil AJ, Kim JC, Mirkin SM. Precarious maintenance of simple DNA repeats in eukaryotes. BioEssays. 2017;39: 1–10. doi: 10.1002/bies.201700077 28703879

157. Barkley LR, Song IY, Zou Y, Vaziri C. Reduced expression of GINS complex members induces hallmarks of pre-malignancy in primary untransformed human cells. Cell Cycle. 2009;8: 1577–1588. doi: 10.4161/cc.8.10.8535 19377277

158. Adams A, Gottschling DE, Kaiser CA, Stearns T. Methods in Yeast Genetics: A Cold Spring Harbor Laboratory Course Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1997.

159. Amberg DC, Burke DJ, Strathern JN. Methods in Yeast Genetics. A Cold Spring Harbor Laboratory Course Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2005.

160. Gietz RD, Woods RA. Transformation of Yeast by the Lithium Acetate/Single-Stranded Carrier DNA/PEG Method [Internet]. Methods in Microbiology. Elsevier; 1998. doi: 10.1016/S0580-9517(08)70325-8

161. Sambrook J, Russell DW. Molecular cloning: a laboratory manual. 3rd ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, c2001.; 2001.

162. Pavlov YI, Newlon CS, Kunkel T a. Yeast origins establish a strand bias for replicational mutagenesis. Mol Cell. 2002;10: 207–213. doi: 10.1016/s1097-2765(02)00567-1 12150920

163. Goldstein AL, McCusker JH. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast. 1999;15: 1541–1553. doi: 10.1002/(SICI)1097-0061(199910)15:14<1541::AID-YEA476>3.0.CO;2-K 10514571

164. Dmowski M, Gołębiewski M, Kern-Zdanowicz I. Characteristics of the Conjugative Transfer System of the IncM Plasmid pCTX-M3 and Identification of Its Putative Regulators. J Bacteriol. American Society for Microbiology Journals; 2018;200: e00234–18. doi: 10.1128/JB.00234-18 29986941

165. Dixon MJ, Bhattacharyya S, Lahue RS. Genetic Assays for Triplet Repeat Instability in Yeast. Trinucleotide Repeat Protoc. 2004;277: 029–046. doi: 10.1385/1-59259-804-8:029

166. Wierdl M, Dominska M, Petes TD. Microsatellite Instability in Yeast: Dependence on the Length of the Microsatellite. Genetics. 1997;779: 769–779.

167. Drake JW. A constant rate of spontaneous mutation in DNA-based microbes. Proc Natl Acad Sci. 1991;88: 7160–7164. doi: 10.1073/pnas.88.16.7160 1831267

168. Krol K, Jendrysek J, Debski J, Skoneczny M, Kurlandzka A, Kaminska J, et al. Ribosomal DNA status inferred from DNA cloud assays and mass spectrometry identification of agarose-squeezed proteins interacting with chromatin (ASPIC-MS). Oncotarget. 2017;5: 24988–25004. doi: 10.18632/oncotarget.15332 28212567

169. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. NIH Public Access; 2012;9: 671–5. doi: 10.1038/nmeth.2089 22930834