Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity

English version České info

The building blocks of DNA, dNTPs, are vital to life, and thus their production is carefully controlled within each cell. Under certain conditions, such as cancer, infection, or drugs, the overall dNTP level or dNTP balance can change. Using yeast genetics we manipulated the dNTP pool balance in unicellular baker's yeast and analysed the effects upon fidelity of DNA replication. We also disrupted mismatch repair, an internal safety system that corrects replication errors and is mutated in many cancers. By sequencing DNA from yeast cells with these alterations we gain insights into the mechanisms of mutation formation that contribute to genome instability. We find that the leading and lagging strand replication fidelity is affected similarly by the dNTP pool imbalance and that the mismatch repair machinery corrects replication errors driven by a dNTP pool imbalance with highly variable efficiencies.

Vyšlo v časopise: Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004846
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004846

Souhrn

Zdroje

1. KunzBA, KohalmiSE, KunkelTA, MathewsCK, McIntoshEM, et al. (1994) International Commission for Protection Against Environmental Mutagens and Carcinogens. Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mutation research 318 : 1–64.

2. Mathews CK (2014) Deoxyribonucleotides as genetic and metabolic regulators. FASEB J. E-pub ahead of print.

3. ReichardP (1988) Interactions between deoxyribonucleotide and DNA synthesis. Annual review of biochemistry 57 : 349–374.

4. ThelanderL (2007) Ribonucleotide reductase and mitochondrial DNA synthesis. Nature genetics 39 : 703–704.

5. ThelanderL, ReichardP (1979) Reduction of ribonucleotides. Annual review of biochemistry 48 : 133–158.

6. HoferA, CronaM, LoganDT, SjobergBM (2012) DNA building blocks: keeping control of manufacture. Critical reviews in biochemistry and molecular biology 47 : 50–63.

7. XuH, FaberC, UchikiT, FairmanJW, RaccaJ, et al. (2006) Structures of eukaryotic ribonucleotide reductase I provide insights into dNTP regulation. Proceedings of the National Academy of Sciences of the United States of America 103 : 4022–4027.

8. YaoNY, SchroederJW, YurievaO, SimmonsLA, O'DonnellME (2013) Cost of rNTP/dNTP pool imbalance at the replication fork. Proceedings of the National Academy of Sciences 110 : 12942–12947.

9. KunkelTA, ErieDA (2005) DNA mismatch repair. Annual review of biochemistry 74 : 681–710.

10. HarfeBD, Jinks-RobertsonS (2000) DNA mismatch repair and genetic instability. Annual review of genetics 34 : 359–399.

11. JohnsonRE, KovvaliGK, PrakashL, PrakashS (1996) Requirement of the Yeast MSH3 and MSH6 Genes for MSH2-dependent Genomic Stability. Journal of Biological Chemistry 271 : 7285–7288.

12. PeltomakiP, VasenHF (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 : 1146–1158.

13. SrivastavaK, SrivastavaA, MittalB (2010) Polymorphisms in ERCC2, MSH2, and OGG1 DNA repair genes and gallbladder cancer risk in a population of Northern India. Cancer 116 : 3160–3169.

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

15. BurgersPMJ (2009) Polymerase Dynamics at the Eukaryotic DNA Replication Fork. Journal of Biological Chemistry 284 : 4041–4045.

16. KumarD, VibergJ, NilssonAK, ChabesA (2010) Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Research 38 : 3975–3983.

17. KumarD, AbdulovicAL, VibergJ, NilssonAK, KunkelTA, et al. (2011) Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Research 39 : 1360–1371.

18. RaghuramanMK, WinzelerEA, CollingwoodD, HuntS, WodickaL, et al. (2001) Replication dynamics of the yeast genome. Science 294 : 115–121.

19. YabukiN, TerashimaH, KitadaK (2002) Mapping of early firing origins on a replication profile of budding yeast. Genes to cells: devoted to molecular & cellular mechanisms 7 : 781–789.

20. KimH-M, NarayananV, MieczkowskiPA, PetesTD, KrasilnikovaMM, et al. (2008) Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J 27 : 2896–2906.

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

22. SereroA, JubinC, LoeilletS, Legoix-NéP, NicolasAG (2014) Mutational landscape of yeast mutator strains. Proceedings of the National Academy of Sciences 111 : 1897–1902 doi:10.1073/pnas.1314423111

23. Lujan SA, Clausen AR, Clark AB, MacAlpine HK, MacAlpine DM, et al. (2014) Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition. Genome Res. doi:10.1101/gr.178335.114

24. KaneDP, ShcherbakovaPV (2014) A common cancer-associated DNA polymerase epsilon mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Research 74 : 1895–1901.

25. Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY, et al. (2014) Exonuclease mutations In DNA Polymerase Epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Research. doi:10.1101/gr.174789.114

26. AlexandrovLB, Nik-ZainalS, WedgeDC, AparicioSA, BehjatiS, et al. (2013) Signatures of mutational processes in human cancer. Nature 500 : 415–421.

27. MuznyDM, BainbridgeMN, ChangK, DinhHH, DrummondJA, et al. (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487 : 330–337.

28. GetzG, GabrielSB, CibulskisK, LanderE, SivachenkoA, et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497 : 67–73.

29. LujanSA, WilliamsJS, PursellZF, Abdulovic-CuiAA, ClarkAB, et al. (2012) Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity. PLoS Genet 8: e1003016.

30. GraggH, HarfeBD, Jinks-RobertsonS (2002) Base composition of mononucleotide runs affects DNA polymerase slippage and removal of frameshift intermediates by mismatch repair in Saccharomyces cerevisiae. Mol Cell Biol 22 : 8756–8762.

31. LehnerK, MudrakSV, MinesingerBK, Jinks-RobertsonS (2012) Frameshift mutagenesis: the roles of primer-template misalignment and the nonhomologous end-joining pathway in Saccharomyces cerevisiae. Genetics 190 : 501–510.

32. SchaaperRM, RadmanM (1989) The extreme mutator effect of Escherichia coli mutD5 results from saturation of mismatch repair by excessive DNA replication errors. The EMBO journal 8 : 3511–3516.

33. 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.

34. DohetC, WagnerR, RadmanM (1985) Repair of defined single base-pair mismatches in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 82 : 503–505.

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

36. SchaaperRM (1993) Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli. The Journal of biological chemistry 268 : 23762–23765.

37. Nick McElhinnySA, KisslingGE, KunkelTA (2010) Differential correction of lagging-strand replication errors made by DNA polymerases {alpha} and {delta}. Proceedings of the National Academy of Sciences of the United States of America 107 : 21070–21075.

38. GueldenerU, HeinischJ, KoehlerGJ, VossD, HegemannJH (2002) A second set of loxP marker cassettes for Cre-mediated multiple gene knockouts in budding yeast. Nucleic Acids Research 30: e23.

39. GoldsteinAL, McCuskerJH (1999) Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 15 : 1541–1553.

40. DrakeJW (1991) A constant rate of spontaneous mutation in DNA-based microbes. Proceedings of the National Academy of Sciences of the United States of America 88 : 7160–7164.

41. LeaDE, CoulsonCA (1949) The distribution of the numbers of mutants in bacterial populations. Journal of genetics 49 : 264–285.

42. HochNC, ChenES, BucklandR, WangSC, FazioA, et al. (2013) Molecular basis of the essential s phase function of the rad53 checkpoint kinase. Molecular and cellular biology 33 : 3202–3213.