Replicative DNA Polymerase δ but Not ε Proofreads Errors in and in

1. Morrison A, Araki H, Clark AB, Hamatake RK, Sugino A. A third essential DNA polymerase in S. cerevisiae. Cell. 1990;62: 1143–1151. 2169349

2. Syvaoja J, Suomensaari S, Nishida C, Goldsmith JS, Chui GS, et al. DNA polymerases α, δ, and ε: three distinct enzymes from HeLa cells. Proc Natl Acad Sci U S A. 1990;87: 6664–6668. 1975694

3. Morrison A, Johnson AL, Johnston LH, Sugino A. Pathway correcting DNA replication errors in Saccharomyces cerevisiae. EMBO J. 1993;12: 1467–1473. 8385605

4. Morrison A, Bell JB, Kunkel TA, Sugino A. Eukaryotic DNA polymerase amino acid sequence required for 3′——5′ exonuclease activity. Proc Natl Acad Sci USA. 1991;88: 9473–9477. 1658784

5. Simon M, Giot L, Faye G. The 3′ to 5′ exonuclease activity located in the DNA polymerase delta subunit of Saccharomyces cerevisiae is required for accurate replication. EMBO J. 1991;10: 2165–2170. 1648480

6. Pavlov YI, Shcherbakova PV. DNA polymerases at the eukaryotic fork-20 years later. Mutat Res. 2010;685: 45–53. doi: 10.1016/j.mrfmmm.2009.08.002 19682465

7. Morrison A, Sugino A. The 3′—>5′ exonucleases of both DNA polymerases delta and epsilon participate in correcting errors of DNA replication in Saccharomyces cerevisiae. Mol Gen Genet. 1994;242: 289–296. 8107676

8. Karthikeyan R, Vonarx EJ, Straffon AFL, Simon M, Faye G, et al. Evidence from mutational specificity studies that yeast DNA polymerases δ and ε replicate different DNA strands at an intracellular replication fork. J Mol Biol. 2000;299: 405–419. 10860748

9. Shcherbakova PV, Pavlov YI. 3′—>5′ exonucleases of DNA polymerases ε and δ correct base analog induced DNA replication errors on opposite DNA strands in Saccharomyces cerevisiae. Genetics. 1996;142: 717–726. 8849882

10. Pavlov YI, Frahm C, Nick McElhinny SA, Niimi A, Suzuki M, et al. Evidence that errors made by DNA polymerase α are corrected by DNA polymerase δ. Curr Biol. 2006;16: 202–207. 16431373

11. Pursell ZF, Isoz I, Lundstrom EB, Johansson E, Kunkel TA. Yeast DNA polymerase ε participates in leading-strand DNA replication. Science. 2007;317: 127–130. 17615360

12. Nick McElhinny SA, Gordenin DA, Stith CM, Burgers PM, Kunkel TA. Division of labor at the eukaryotic replication fork. Mol Cell. 2008;30: 137–144. doi: 10.1016/j.molcel.2008.02.022 18439893

13. Larrea AA, Lujan SA, Nick McElhinny SA, Mieczkowski PA, Resnick MA, et al. Genome-wide model for the normal eukaryotic DNA replication fork. Proc Natl Acad Sci U S A. 2010;107: 17674–17679. doi: 10.1073/pnas.1010178107 20876092

14. Miyabe I, Kunkel TA, Carr AM. The major roles of DNA polymerases epsilon and delta at the eukaryotic replication fork are evolutionarily conserved. PLoS Genet. 2011;7: e1002407. doi: 10.1371/journal.pgen.1002407 22144917

15. Kesti T, Flick K, Keränen S, Syväoja JE, Wittenberg C. DNA polymerase ε catalytic domains are dispensable for DNA replication, DNA repair, and cell viability. Mol Cell. 1999;3: 679–685. 10360184

16. Pavlov YI, Maki S, Maki H, Kunkel TA. Evidence for interplay among yeast replicative DNA polymerases alpha, delta and epsilon from studies of exonuclease and polymerase active site mutations. BMC Biol. 2004;2: 11. 15163346

17. 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

18. Tran HT, Gordenin DA, Resnick MA. The 3′—>5′ exonucleases of DNA polymerases δ and ε and the 5′—>3′ exonuclease Exo1 have major roles in postreplication mutation avoidance in Saccharomyces cerevisiae. Mol Cell Biol. 1999;19: 2000–2007. 10022887

19. Garg P, Burgers PMJ. DNA polymerases that propagate the eukaryotic DNA replication fork. Crit Rev Biochem Mol Biol. 2005;40: 115–128. 15814431

20. Kunkel TA, Burgers PM. Dividing the workload at a eukaryotic replication fork. Trends Cell Biol. 2008;18: 521–527. doi: 10.1016/j.tcb.2008.08.005 18824354

21. Iyer RR, Pluciennik A, Burdett V, Modrich PL. DNA mismatch repair: functions and mechanisms. Chem Rev. 2006;106: 302–323. 16464007

22. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7: 335–346. 16612326

23. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18: 85–98. 18157157

24. Harrington JM, Kolodner RD. Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs. Mol Cell Biol. 2007;27: 6546–6554. 17636021

25. Romanova NV, Crouse GF. Different roles of eukaryotic MutS and MutL complexes in repair of small insertion and deletion loops in yeast. PLoS Genet. 2013;9: e1003920. doi: 10.1371/journal.pgen.1003920 24204320

26. Pluciennik A, Dzantiev L, Iyer RR, Constantin N, Kadyrov FA, et al. PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair. Proc Natl Acad Sci USA. 2010;107: 16066–16071. doi: 10.1073/pnas.1010662107 20713735

27. Kadyrov FA, Holmes SF, Arana ME, Lukianova OA, O’Donnell M, et al. Saccharomyces cerevisiae MutLα Is a mismatch repair endonuclease. J Biol Chem. 2007;282: 37181–37190. 17951253

28. Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLα in human mismatch repair. Cell. 2006;126: 297–308. 16873062

29. Ghodgaonkar MM, Lazzaro F, Olivera-Pimentel M, Artola-Boran M, Cejka P, et al. Ribonucleotides misincorporated into DNA act as strand-discrimination signals in eukaryotic mismatch repair. Mol Cell. 2013;50: 323–332. doi: 10.1016/j.molcel.2013.03.019 23603115

30. Lujan SA, Williams JS, Clausen AR, Clark AB, Kunkel TA. Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol Cell. 2013;50: 437–443. doi: 10.1016/j.molcel.2013.03.017 23603118

31. Kunkel TA, Bebenek K. DNA replication fidelity. Annu Rev Biochem. 2000;69: 497–529. 10966467

32. Shcherbakova PV, Pavlov YI, Chilkova O, Rogozin IB, Johansson E, et al. Unique error signature of the four-subunit yeast DNA polymerase ε. J Biol Chem. 2003;278: 43770–43780. 12882968

33. Fortune JM, Pavlov YI, Welch CM, Johansson E, Burgers PM, et al. Saccharomyces cerevisiae DNA polymerase δ: high fidelity for base substitutions but lower fidelity for single- and multi-base deletions. J Biol Chem. 2005;280: 29980–29987. 15964835

34. Huang MM, Arnheim N, Goodman MF. Extension of base mispairs by Taq DNA polymerase: implications for single nucleotide discrimination in PCR. Nucleic Acids Res. 1992;20: 4567–4573. 1408758

35. Joyce CM, Sun XC, Grindley ND. Reactions at the polymerase active site that contribute to the fidelity of Escherichia coli DNA polymerase I (Klenow fragment). J Biol Chem. 1992;267: 24485–24500. 1447195

36. Johnson SJ, Beese LS. Structures of mismatch replication errors observed in a DNA polymerase. Cell. 2004;116: 803–816. 15035983

37. Williams T-M, Fabbri RM, Reeves JW, Crouse GF. A new reversion assay for measuring all possible base pair substitutions in Saccharomyces cerevisiae. Genetics. 2005;170: 1423–1426. 15911571

38. Pavlov YI, Mian IM, Kunkel TA. Evidence for preferential mismatch repair of lagging strand DNA replication errors in yeast. Curr Biol. 2003;13: 744–748. 12725731

39. Kow YW, Bao G, Reeves JW, Jinks-Robertson S, Crouse GF. Oligonucleotide transformation of yeast reveals mismatch repair complexes to be differentially active on DNA replication strands. Proc Natl Acad Sci USA. 2007;104: 11352–11357. 17592146

40. Williams LN, Herr AJ, Preston BD. Emergence of DNA polymerase ε antimutators that escape error-induced extinction in yeast. Genetics. 2013;193: 751–770. doi: 10.1534/genetics.112.146910 23307893

41. Jin YH, Garg P, Stith CMW, Al Refai H, Sterling JF, et al. The multiple biological roles of the 3′—>5′ exonuclease of Saccharomyces cerevisiae DNA polymerase δ require switching between the polymerase and exonuclease domains. Mol Cell Biol. 2005;25: 461–471. 15601866

42. Jin YH, Ayyagari R, Resnick MA, Gordenin DA, Burgers PMJ. Okazaki fragment maturation in yeast—II. Cooperation between the polymerase and 3′-5′-exonuclease activities of Pol δ in the creation of a ligatable nick. J Biol Chem. 2003;278: 1626–1633. 12424237

43. Jin YH, Obert R, Burgers PMJ, Kunkel TA, Resnick MA, et al. The 3′—>5′ exonuclease of DNA polymerase δ can substitute for the 5′ flap endonuclease Rad27/Fen1 in processing Okazaki fragments and preventing genome instability. Proc Natl Acad Sci USA. 2001;98: 5122–5127. 11309502

44. Nick McElhinny SA, Pavlov YI, Kunkel TA. Evidence for extrinsic exonucleolytic proofreading. Cell Cycle. 2006;5: 958–962. 16687920

45. Tran HT, Degtyareva NP, Gordenin DA, Resnick MA. Genetic factors affecting the impact of DNA polymerase δ proofreading activity on mutation avoidance in yeast. Genetics. 1999;152: 47–59. 10224242

46. Datta A, Schmeits JL, Amin NS, Lau PJ, Myung K, et al. Checkpoint-dependent activation of mutagenic repair in Saccharomyces cerevisiae pol3–01 mutants. Mol Cell. 2000;6: 593–603. 11030339

47. Aksenova A, Volkov K, Maceluch J, Pursell ZF, Rogozin IB, et al. Mismatch repair-independent increase in spontaneous mutagenesis in yeast lacking non-essential subunits of DNA polymerase ε. PLoS Genet. 2010;6: e1001209. doi: 10.1371/journal.pgen.1001209 21124948

48. Herr AJ, Ogawa M, Lawrence NA, Williams LN, Eggington JM, et al. Mutator suppression and escape from replication error-induced extinction in yeast. PLoS Genet. 2011;7: e1002282. doi: 10.1371/journal.pgen.1002282 22022273

49. Kane DP, Shcherbakova PV. A common cancer-associated DNA polymerase ε mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res. 2014;74: 1895–1901. doi: 10.1158/0008-5472.CAN-13-2892 24525744

50. Herr AJ, Kennedy SR, Knowels GM, Schultz EM, Preston BD. DNA replication error-induced extinction of diploid yeast. Genetics. 2014;196: 677–691. doi: 10.1534/genetics.113.160960 24388879

51. Tran HT, Keen JD, Kricker M, Resnick MA, Gordenin DA. Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol Cell Biol. 1997;17: 2859–2865. 9111358

52. Babudri N, Pavlov YI, Matmati N, Ludovisi C, Achilli A. Stationary-phase mutations in proofreading exonuclease-deficient strains of the yeast Saccharomyces cerevisiae. Mol Gen Genet. 2001;265: 362–366.

53. Krzywinski M, Altman N. Points of significance: error bars. Nat Methods. 2013;10: 921–922. doi: 10.1038/nmeth.2659 24161969

54. Carr PA, Wang HH, Sterling B, Isaacs FJ, Lajoie MJ, et al. Enhanced multiplex genome engineering through co-operative oligonucleotide co-selection. Nucleic Acids Res. 2012;40: e132. 22638574

55. Lajoie MJ, Gregg CJ, Mosberg JA, Washington GC, Church GM. Manipulating replisome dynamics to enhance lambda Red-mediated multiplex genome engineering. Nucleic Acids Res. 2012;40: e170. doi: 10.1093/nar/gks751 22904085

56. Sawitzke JA, Costantino N, Li XT, Thomason LC, Bubunenko M, et al. Probing cellular processes with oligo-mediated recombination and using the knowledge gained to optimize recombineering. J Mol Biol. 2011;407: 45–59. doi: 10.1016/j.jmb.2011.01.030 21256136

57. Wang HH, Xu G, Vonner AJ, Church G. Modified bases enable high-efficiency oligonucleotide-mediated allelic replacement via mismatch repair evasion. Nucleic Acids Res. 2011;39: 7336–7347. doi: 10.1093/nar/gkr183 21609953

58. Murphy KC, Marinus MG. RecA-independent single-stranded DNA oligonucleotide-mediated mutagenesis. F1000 Biol Rep. 2010;2: 56. 20711416

59. Lu LY, Huen MS, Tai AC, Liu DP, Cheah KS, et al. Highly efficient deletion method for the engineering of plasmid DNA with single-stranded oligonucleotides. BioTechniques. 2008;44: 217–224. 18330349

60. Costantino N, Court DL. Enhanced levels of lambda red-mediated recombinants in mismatch repair mutants. Proc Natl Acad Sci USA. 2003;100: 15748–15753. 14673109

61. Li XT, Costantino N, Lu LY, Liu DP, Watt RM, et al. Identification of factors influencing strand bias in oligonucleotide-mediated recombination in Escherichia coli. Nucleic Acids Res. 2003;31: 6674–6687. 14602928

62. Huen MS, Li XT, Lu LY, Watt RM, Liu DP, et al. The involvement of replication in single stranded oligonucleotide-mediated gene repair. Nucleic Acids Res. 2006;34: 6183–6194. 17088285

63. Rios X, Briggs AW, Christodoulou D, Gorham JM, Seidman JG, et al. Stable gene targeting in human cells using single-strand oligonucleotides with modified bases. PLoS ONE. 2012;7: e36697. doi: 10.1371/journal.pone.0036697 22615794

64. Olsen PA, Randol M, Luna L, Brown T, Krauss S. Genomic sequence correction by single-stranded DNA oligonucleotides: role of DNA synthesis and chemical modifications of the oligonucleotide ends. J Gene Med. 2005;7: 1534–1544. 16025558

65. Wu XS, Xin L, Yin WX, Shang XY, Lu L, et al. Increased efficiency of oligonucleotide-mediated gene repair through slowing replication fork progression. Proc Natl Acad Sci USA. 2005;102: 2508–2513. 15695590

66. McLachlan J, Fernandez S, Helleday T, Bryant HE. Specific targeted gene repair using single-stranded DNA oligonucleotides at an endogenous locus in mammalian cells uses homologous recombination. DNA Repair (Amst). 2009;8: 1424–1433. doi: 10.1016/j.dnarep.2009.09.014 19854687

67. Olsen PA, Randol M, Krauss S. Implications of cell cycle progression on functional sequence correction by short single-stranded DNA oligonucleotides. Gene Ther. 2005;12: 546–551. 15674399

68. Radecke S, Radecke F, Peter I, Schwarz K. Physical incorporation of a single-stranded oligodeoxynucleotide during targeted repair of a human chromosomal locus. J Gene Med. 2006;8: 217–228. 16142817

69. Aarts M, te Riele H. Progress and prospects: oligonucleotide-directed gene modification in mouse embryonic stem cells: a route to therapeutic application. Gene Ther. 2011;18: 213–219. doi: 10.1038/gt.2010.161 21160530

70. Aarts M, te Riele H. Subtle gene modification in mouse ES cells: evidence for incorporation of unmodified oligonucleotides without induction of DNA damage. Nucleic Acids Res. 2010;38: 6956–6967. doi: 10.1093/nar/gkq589 20601408

71. Zhang Y, Muyrers JP, Rientjes J, Stewart AF. Phage annealing proteins promote oligonucleotide-directed mutagenesis in Escherichia coli and mouse ES cells. BMC Mol Biol. 2003;4: 1. 12530927

72. Dekker M, de Vries S, Aarts M, Dekker R, Brouwers C, et al. Transient suppression of MLH1 allows effective single-nucleotide substitution by single-stranded DNA oligonucleotides. Mutat Res. 2011;715: 52–60. doi: 10.1016/j.mrfmmm.2011.07.008 21801734

73. Wielders EA, Dekker RJ, Holt I, Morris GE, te Riele H. Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. Hum Mutat. 2011;32: 389–396. doi: 10.1002/humu.21448 21309037

74. Aarts M, Dekker M, Dekker R, de Vries S, van der Wal A, et al. Gene modification in embryonic stem cells by single-stranded DNA oligonucleotides. Methods Mol Biol. 2009;530: 79–99. doi: 10.1007/978-1-59745-471-1_5 19266328

75. Olsen PA, Solhaug A, Booth JA, Gelazauskaite M, Krauss S. Cellular responses to targeted genomic sequence modification using single-stranded oligonucleotides and zinc-finger nucleases. DNA Repair (Amst). 2009;8: 298–308. doi: 10.1016/j.dnarep.2008.11.011 19071233

76. Papaioannou I, Disterer P, Owen JS. Use of internally nuclease-protected single-strand DNA oligonucleotides and silencing of the mismatch repair protein, MSH2, enhances the replication of corrected cells following gene editing. J Gene Med. 2009;11: 267–274. doi: 10.1002/jgm.1296 19153972

77. Igoucheva O, Alexeev V, Anni H, Rubin E. Oligonucleotide-mediated gene targeting in human hepatocytes: implications of mismatch repair. Oligonucleotides. 2008;18: 111–122. doi: 10.1089/oli.2008.0120 18637729

78. Huen MS, Lu LY, Liu DP, Huang JD. Active transcription promotes single-stranded oligonucleotide mediated gene repair. Biochem Biophys Res Commun. 2007;353: 33–39. 17174937

79. Aarts M, Dekker M, de Vries S, van der Wal A, te Riele H. Generation of a mouse mutant by oligonucleotide-mediated gene modification in ES cells. Nucleic Acids Res. 2006;34: e147. 17142234

80. Dekker M, Brouwers C, Aarts M, van der Torre J, de Vries S, et al. Effective oligonucleotide-mediated gene disruption in ES cells lacking the mismatch repair protein MSH3. Gene Ther. 2006;13: 686–694. 16437133

81. Dekker M, Brouwers C, te Riele H. Targeted gene modification in mismatch-repair-deficient embryonic stem cells by single-stranded DNA oligonucleotides. Nucleic Acids Res. 2003;31: e27. 12626726

82. Rodriguez GP, Song JB, Crouse GF. In Vivo bypass of 8-oxodG. PLoS Genet. 2013;9: e1003682. doi: 10.1371/journal.pgen.1003682 23935538

83. Rodriguez GP, Romanova NV, Bao G, Rouf NC, Kow YW, et al. Mismatch repair dependent mutagenesis in nondividing cells. Proc Natl Acad Sci USA. 2012;109: 6153–6158. doi: 10.1073/pnas.1115361109 22474380

84. Rodriguez GP, Song JB, Crouse GF. Transformation with oligonucleotides creating clustered changes in the yeast genome. PLoS ONE. 2012;7: e42905. doi: 10.1371/journal.pone.0042905 22916177

85. Gabbai CB, Yeeles JT, Marians KJ. Replisome-mediated Translesion Synthesis and Leading Strand Template Lesion Skipping Are Competing Bypass Mechanisms. J Biol Chem. 2014;289: 32811–32823. doi: 10.1074/jbc.M114.613257 25301949

86. Yeeles JT. Discontinuous leading-strand synthesis: a stop-start story. Biochem Soc Trans. 2014;42: 25–34. doi: 10.1042/BST20130262 24450623

87. Mojas N, Lopes M, Jiricny J. Mismatch repair-dependent processing of methylation damage gives rise to persistent single-stranded gaps in newly replicated DNA. Genes Dev. 2007;21: 3342–3355. 18079180

88. Georgescu RE, Langston L, Yao NY, Yurieva O, Zhang D, et al. Mechanism of asymmetric polymerase assembly at the eukaryotic replication fork. Nat Struct Mol Biol. 2014;21: 664–670. doi: 10.1038/nsmb.2851 24997598

89. Kunkel TA, Burgers PM. Delivering nonidentical twins. Nat Struct Mol Biol. 2014;21: 649–651. doi: 10.1038/nsmb.2852 24997601

90. Kamiya H. Mutagenicity of oxidized DNA precursors in living cells: Roles of nucleotide pool sanitization and DNA repair enzymes, and translesion synthesis DNA polymerases. Mutat Res. 2010;703: 32–36. doi: 10.1016/j.mrgentox.2010.06.003 20542139

91. Wyrzykowski J, Volkert MR. The Escherichia coli methyl-directed mismatch repair system repairs base pairs containing oxidative lesions. J Bacteriol. 2003;185: 1701–1704. 12591888

92. Colussi C, Parlanti E, Degan P, Aquilina G, Barnes D, et al. The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool. Curr Biol. 2002;12: 912–918. 12062055

93. Ni TT, Marsischky GT, Kolodner RD. MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. Mol Cell. 1999;4: 439–444. 10518225

94. Morrison A, Sugino A. Roles of POL3, POL2 and PMS1 genes in maintaining accurate DNA replication. Chromosoma. 1992;102: S147–S149. 1291235

95. Marsischky GT, Kolodner RD. Biochemical characterization of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 complex and mispaired bases in DNA. J Biol Chem. 1999;274: 26668–26682. 10480869

96. Shockley AH, Doo DW, Rodriguez GP, Crouse GF. Oxidative damage and mutagenesis in Saccharomyces cerevisiae: genetic studies of pathways affecting replication fidelity of 8-oxoguanine. Genetics. 2013;195: 359–367. doi: 10.1534/genetics.113.153874 23893481

97. Earley MC, Crouse GF. The role of mismatch repair in the prevention of base pair mutations in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 1998;95: 15487–15491. 9860995

98. Mendelman LV, Petruska J, Goodman MF. Base mispair extension kinetics. Comparison of DNA polymerase α and reverse transcriptase. J Biol Chem. 1990;265: 2338–2346. 1688852

99. Ventura I, Russo MT, De LG, Bignami M. Oxidized purine nucleotides, genome instability and neurodegeneration. Mutat Res. 2010;703: 59–65. doi: 10.1016/j.mrgentox.2010.06.008 20601098

100. Lujan SA, Williams JS, Pursell ZF, Abdulovic-Cui AA, Clark AB, et al. Mismatch repair balances leading and lagging strand DNA replication fidelity. PLoS Genet. 2012;8: e1003016. doi: 10.1371/journal.pgen.1003016 23071460

101. Fijalkowska IJ, Schaaper RM. Mutants in the Exo I motif of Escherichia coli dnaQ: Defective proofreading and inviability due to error catastrophe. Proc Natl Acad Sci USA. 1996;93: 2856–2861. 8610131

102. Longley MJ, Pierce AJ, Modrich P. DNA polymerase δ is required for human mismatch repair in vitro. J Biol Chem. 1997;272: 10917–10921. 9099749

103. Kadyrov FA, Genschel J, Fang Y, Penland E, Edelmann W, et al. A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair. Proc Natl Acad Sci USA. 2009;106: 8495–8500. doi: 10.1073/pnas.0903654106 19420220

104. Modrich P. Mechanisms in eukaryotic mismatch repair. J Biol Chem. 2006;281: 30305–30309. 16905530

105. Prindle MJ, Loeb LA. DNA polymerase delta in DNA replication and genome maintenance. Environ Mol Mutagen. 2012;53: 666–682. doi: 10.1002/em.21745 23065663

106. Lujan SA, Clausen AR, Clark AB, MacAlpine HK, MacAlpine DM, et al. Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition. Genome Res. 2014.

107. Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, et al. DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22: 2820–2828. doi: 10.1093/hmg/ddt131 23528559

108. Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45: 136–144. doi: 10.1038/ng.2503 23263490

109. Heitzer E, Tomlinson I. Replicative DNA polymerase mutations in cancer. Curr Opin Genet Dev. 2014;24: 107–113. doi: 10.1016/j.gde.2013.12.005 24583393

110. Meng B, Hoang LN, McIntyre JB, Duggan MA, Nelson GS, et al. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol. 2014.

111. Albertson TM, Ogawa M, Bugni JM, Hays LE, Chen Y, et al. DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci USA. 2009;106: 17101–17104. doi: 10.1073/pnas.0907147106 19805137

112. Goldsby RE, Hays LE, Chen X, Olmsted EA, Slayton WB, et al. High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading. Proc Natl Acad Sci USA. 2002;99: 15560–15565. 12429860

113. Edelmann W, Yang K, Umar A, Heyer J, Kirkland L, et al. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell. 1997;91: 467–477. 9390556

114. Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102: 193–201. doi: 10.1093/jnci/djp473 20028993

115. Brachmann CB, Davies A, Cost GJ, Caputo E, Li JC, et al. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast. 1998;14: 115–132. 9483801

116. Storici F, Lewis LK, Resnick MA. In vivo site-directed mutagenesis using oligonucleotides. Nat Biotechnol. 2001;19: 773–776. 11479573

117. Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K, et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science. 1999;285: 901–906. 10436161

118. Güldener U, Heck S, Fiedler T, Beinhauer J, Hegemann JH. A new efficient gene disruption cassette for repeated use in budding yeast. Nucleic Acids Res. 1996;24: 2519–2524. 8692690

119. Carter Z, Delneri D. New generation of loxP-mutated deletion cassettes for the genetic manipulation of yeast natural isolates. Yeast. 2010;27: 765–775. doi: 10.1002/yea.1774 20641014

120. Sherman F. Getting started with yeast. Methods Enzymol. 1991;194: 3–21. 2005794

121. Zheng Q. On Haldane′s formulation of Luria and Delbruck′s mutation model. Math Biosci. 2007;209: 500–513. 17462675

122. Zheng Q. New algorithms for Luria-Delbruck fluctuation analysis. Math Biosci. 2005;196: 198–214. 15950991

123. Zheng Q. Statistical and algorithmic methods for fluctuation analysis with SALVADOR as an implementation. Math Biosci. 2002;176: 237–252. 11916511