Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity

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The two DNA strands of the nuclear genome are replicated asymmetrically using three DNA polymerases, α, δ, and ε. Current evidence suggests that DNA polymerase ε (Pol ε) is the primary leading strand replicase, whereas Pols α and δ primarily perform lagging strand replication. The fact that these polymerases differ in fidelity and error specificity is interesting in light of the fact that the stability of the nuclear genome depends in part on the ability of mismatch repair (MMR) to correct different mismatches generated in different contexts during replication. Here we provide the first comparison, to our knowledge, of the efficiency of MMR of leading and lagging strand replication errors. We first use the strand-biased ribonucleotide incorporation propensity of a Pol ε mutator variant to confirm that Pol ε is the primary leading strand replicase in Saccharomyces cerevisiae. We then use polymerase-specific error signatures to show that MMR efficiency in vivo strongly depends on the polymerase, the mismatch composition, and the location of the mismatch. An extreme case of variation by location is a T-T mismatch that is refractory to MMR. This mismatch is flanked by an AT-rich triplet repeat sequence that, when interrupted, restores MMR to >95% efficiency. Thus this natural DNA sequence suppresses MMR, placing a nearby base pair at high risk of mutation due to leading strand replication infidelity. We find that, overall, MMR most efficiently corrects the most potentially deleterious errors (indels) and then the most common substitution mismatches. In combination with earlier studies, the results suggest that significant differences exist in the generation and repair of Pol α, δ, and ε replication errors, but in a generally complementary manner that results in high-fidelity replication of both DNA strands of the yeast nuclear genome.

Vyšlo v časopise: Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity. PLoS Genet 8(10): e32767. doi:10.1371/journal.pgen.1003016
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003016

Souhrn

Zdroje

1. KunkelTA (2004) DNA replication fidelity. J Biol Chem 279 : 16895–16898.

2. Nick McElhinnySA, GordeninDA, StithCM, BurgersPM, KunkelTA (2008) Division of labor at the eukaryotic replication fork. Mol Cell 30 : 137–144.

3. KunkelTA, ErieDA (2005) DNA mismatch repair. Annu Rev Biochem 74 : 681–710.

4. IyerRR, PluciennikA, BurdettV, ModrichPL (2006) DNA mismatch repair: functions and mechanisms. Chem Rev 106 : 302–323.

5. HsiehP, YamaneK (2008) DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev 129 : 391–407.

6. JiricnyJ (2006) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7 : 335–346.

7. LiGM (2008) Mechanisms and functions of DNA mismatch repair. Cell Res 18 : 85–98.

8. PavlovYI, MianIM, KunkelTA (2003) Evidence for preferential mismatch repair of lagging strand DNA replication errors in yeast. Curr Biol 13 : 744–748.

9. BurgersPM (2009) Polymerase dynamics at the eukaryotic DNA replication fork. J Biol Chem 284 : 4041–4045.

10. McCullochSD, KunkelTA (2008) The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 18 : 148–161.

11. KunkelTA, BurgersPM (2008) Dividing the workload at a eukaryotic replication fork. Trends Cell Biol 18 : 521–527.

12. PavlovYI, ShcherbakovaPV (2010) DNA polymerases at the eukaryotic fork-20 years later. Mutat Res 685 : 45–53.

13. PursellZF, IsozI, LundstromEB, JohanssonE, KunkelTA (2007) Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 317 : 127–130.

14. MiyabeI, KunkelTA, CarrAM (2011) The major roles of DNA polymerases epsilon and delta at the eukaryotic replication fork are evolutionarily conserved. PLoS Genet 7: e1002407 doi:10.1371/journal.pgen.1002407

15. MorrisonA, BellJB, KunkelTA, SuginoA (1991) Eukaryotic DNA polymerase amino acid sequence required for 3′–5′ exonuclease activity. Proc Natl Acad Sci U S A 88 : 9473–9477.

16. MorrisonA, JohnsonAL, JohnstonLH, SuginoA (1993) Pathway correcting DNA replication errors in Saccharomyces cerevisiae. Embo J 12 : 1467–1473.

17. MorrisonA, SuginoA (1994) The 3′–>5′ exonucleases of both DNA polymerases delta and epsilon participate in correcting errors of DNA replication in Saccharomyces cerevisiae. Mol Gen Genet 242 : 289–296.

18. NiimiA, LimsirichaikulS, YoshidaS, IwaiS, MasutaniC, et al. (2004) Palm mutants in DNA polymerases alpha and eta alter DNA replication fidelity and translesion activity. Mol Cell Biol 24 : 2734–2746.

19. PavlovYI, FrahmC, Nick McElhinnySA, NiimiA, SuzukiM, et al. (2006) Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta. Curr Biol 16 : 202–207.

20. AlbertsonTM, OgawaM, BugniJM, HaysLE, ChenY, et al. (2009) DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci U S A 106 : 17101–17104.

21. Nick McElhinnySA, KisslingGE, KunkelTA (2010) Differential correction of lagging-strand replication errors made by DNA polymerases {alpha} and {delta}. Proc Natl Acad Sci U S A 107 : 21070–21075.

22. UmarA, BuermeyerAB, SimonJA, ThomasDC, ClarkAB, et al. (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87 : 65–73.

23. Nick McElhinnySA, KumarD, ClarkAB, WattDL, WattsBE, et al. (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6 : 774–781.

24. PoloumienkoA, DershowitzA, DeJ, NewlonCS (2001) Completion of replication map of Saccharomyces cerevisiae chromosome III. Mol Biol Cell 12 : 3317–3327.

25. LarreaAA, LujanSA, Nick McElhinnySA, MieczkowskiPA, ResnickMA, et al. (2010) Genome-wide model for the normal eukaryotic DNA replication fork. Proc Natl Acad Sci U S A 107 : 17674–17679.

26. KramerB, KramerW, FritzHJ (1984) Different base/base mismatches are corrected with different efficiencies by the methyl-directed DNA mismatch-repair system of E. coli. Cell 38 : 879–887.

27. DohetC, WagnerR, RadmanM (1985) Repair of defined single base-pair mismatches in Escherichia coli. Proc Natl Acad Sci U S A 82 : 503–505.

28. SchaaperRM, DunnRL (1991) Spontaneous mutation in the Escherichia coli lacI gene. Genetics 129 : 317–326.

29. SchaaperRM (1993) Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli. J Biol Chem 268 : 23762–23765.

30. McMurrayCT (2010) Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11 : 786–799.

31. ClarkAB, LujanSA, KisslingGE, KunkelTA (2011) Mismatch repair-independent tandem repeat sequence instability resulting from ribonucleotide incorporation by DNA polymerase epsilon. DNA Repair (Amst) 10 : 476–482.

32. JonesM, WagnerR, RadmanM (1987) Repair of a mismatch is influenced by the base composition of the surrounding nucleotide sequence. Genetics 115 : 605–610.

33. SuSS, LahueRS, AuKG, ModrichP (1988) Mispair specificity of methyl-directed DNA mismatch correction in vitro. J Biol Chem 263 : 6829–6835.

34. MarsischkyGT, KolodnerRD (1999) Biochemical characterization of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 complex and mispaired bases in DNA. J Biol Chem 274 : 26668–26682.

35. WarrenJJ, PohlhausTJ, ChangelaA, IyerRR, ModrichPL, et al. (2007) Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell 26 : 579–592.

36. WangH, YangY, SchofieldMJ, DuC, FridmanY, et al. (2003) DNA bending and unbending by MutS govern mismatch recognition and specificity. Proc Natl Acad Sci U S A 100 : 14822–14827.

37. OhshimaK, KangS, LarsonJE, WellsRD (1996) TTA.TAA triplet repeats in plasmids form a non-H bonded structure. J Biol Chem 271 : 16784–16791.

38. TrottaE, Del GrossoN, ErbaM, PaciM (2000) The ATT strand of AAT.ATT trinucleotide repeats adopts stable hairpin structures induced by minor groove binding ligands. Biochemistry 39 : 6799–6808.

39. TrottaE, Del GrossoN, ErbaM, MelinoS, CiceroD, et al. (2003) Interaction of DAPI with individual strands of trinucleotide repeats. Effects of replication in vitro of the AAT x ATT triplet. Eur J Biochem 270 : 4755–4761.

40. Lopez CastelA, ClearyJD, PearsonCE (2010) Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 11 : 165–170.

41. LiF, TianL, GuL, LiGM (2009) Evidence that nucleosomes inhibit mismatch repair in eukaryotic cells. J Biol Chem 284 : 33056–33061.

42. JavaidS, ManoharM, PunjaN, MooneyA, OttesenJJ, et al. (2009) Nucleosome remodeling by hMSH2-hMSH6. Mol Cell 36 : 1086–1094.

43. GormanJ, PlysAJ, VisnapuuML, AlaniE, GreeneEC (2010) Visualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice. Nat Struct Mol Biol 17 : 932–938.

44. KadyrovaLY, BlankoER, KadyrovFA (2011) CAF-I-dependent control of degradation of the discontinuous strands during mismatch repair. Proc Natl Acad Sci U S A 108 : 2753–2758.

45. WidomJ (2001) Role of DNA sequence in nucleosome stability and dynamics. Q Rev Biophys 34 : 269–324.

46. SegalE, Fondufe-MittendorfY, ChenL, ThastromA, FieldY, et al. (2006) A genomic code for nucleosome positioning. Nature 442 : 772–778.

47. GordeninDA, ResnickMA (1998) Yeast ARMs (DNA at-risk motifs) can reveal sources of genome instability. Mutat Res 400 : 45–58.

48. SyvaojaJ, LinnS (1989) Characterization of a large form of DNA polymerase delta from HeLa cells that is insensitive to proliferating cell nuclear antigen. J Biol Chem 264 : 2489–2497.

49. ChuiG, LinnS (1995) Further characterization of HeLa DNA polymerase epsilon. J Biol Chem 270 : 7799–7808.

50. ChilkovaO, StenlundP, IsozI, StithCM, GrabowskiP, et al. (2007) The eukaryotic leading and lagging strand DNA polymerases are loaded onto primer-ends via separate mechanisms but have comparable processivity in the presence of PCNA. Nucleic Acids Res 35 : 6588–6597.

51. TranHT, GordeninDA, ResnickMA (1999) 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 19 : 2000–2007.

52. KleczkowskaHE, MarraG, LettieriT, JiricnyJ (2001) hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes Dev 15 : 724–736.

53. PluciennikA, DzantievL, IyerRR, ConstantinN, KadyrovFA, et al. (2010) PCNA function in the activation and strand direction of MutLalpha endonuclease in mismatch repair. Proc Natl Acad Sci U S A 107 : 16066–16071.

54. FortuneJM, PavlovYI, WelchCM, JohanssonE, BurgersPM, et al. (2005) Saccharomyces cerevisiae DNA polymerase delta: high fidelity for base substitutions but lower fidelity for single -⁠ and multi-base deletions. J Biol Chem 280 : 29980–29987.

55. Nick McElhinnySA, PavlovYI, KunkelTA (2006) Evidence for extrinsic exonucleolytic proofreading. Cell Cycle 5 : 958–962.

56. SchererS, DavisRW (1979) Replacement of chromosome segments with altered DNA sequences constructed in vitro. Proc Natl Acad Sci U S A 76 : 4951–4955.