MMS Exposure Promotes Increased MtDNA Mutagenesis in the Presence of Replication-Defective Disease-Associated DNA Polymerase γ Variants

English version České info

Thousands of mitochondrial DNA (mtDNA) per cell are necessary to maintain energy required for cellular survival in humans. Interfering with the mtDNA polymerase can result in mitochondrial diseases and mitochondrial toxicity. Therefore, it is important to explore new genetic and environmental mechanisms that alter the effectiveness and accuracy of mtDNA replication. This genetic study uses the budding yeast to demonstrate that heterozygous strains harboring disease-associated mutations in the mtDNA polymerase gene in the presence of a wild type copy of the mtDNA polymerase are associated with increased mtDNA point mutagenesis in the presence of methane methylsulfonate, a known base damaging agent. Further observations suggest that the inability of disease-associated variants to replicate mtDNA resulted in increased vulnerability to irreparable base damage that was likely to result in mutations when replicated. Also, this study showed that trace amounts of the environmental contaminant cadmium chloride impairs mtDNA replication but eliminates damage-induced mutagenesis in the remaining functional mitochondria. This interplay between disease-associated variant and wild type polymerase offers new insights on possible disease variation and implicates novel environmental consequences for compound heterozygous patients.

Vyšlo v časopise: MMS Exposure Promotes Increased MtDNA Mutagenesis in the Presence of Replication-Defective Disease-Associated DNA Polymerase γ Variants. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004748
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004748

Souhrn

Zdroje

1. TrifunovicA, WredenbergA, FalkenbergM, SpelbrinkJN, RovioAT, et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.

2. KujothGC, HionaA, PughTD, SomeyaS, PanzerK, et al. (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481–484.

3. SafdarA, BourgeoisJM, OgbornDI, LittleJP, HettingaBP, et al. (2011) Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A 108: 4135–4140.

4. Van GoethemG, DermautB, LofgrenA, MartinJJ, Van BroeckhovenC (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28: 211–212.

5. ChanSSL, LongleyMJ, CopelandWC (2005) The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem 280: 31341–31346.

6. ChanSSL, LongleyMJ, CopelandWC (2006) Modulation of the W748S mutation in DNA polymerase {gamma} by the E1143G polymorphism in mitochondrial disorders. Hum Mol Genet 15: 3473–3483.

7. ChanSSL, LongleyMJ, NaviauxRK, CopelandWC (2005) Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. DNA Repair 4: 1381–1389.

8. StuartGR, SantosJH, StrandMK, Van HoutenB, CopelandWC (2006) Mitochondrial DNA defects in S. cerevisiae with mutations in DNA polymerase gamma associated with Progressive External Ophthalmolplegia. Hum Mol Genet 15: 363–374.

9. StumpfJD, BaileyCM, SpellD, StillwagonM, AndersonKS, et al. (2010) mip1 Containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. Hum Mol Genet 19: 2123–2133.

10. SzczepanowskaK, FouryF (2010) A cluster of pathogenic mutations in the 3′-5′ exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation. Hum Mol Genet 19: 3516–3529.

11. LongleyMJ, ClarkS, Yu Wai ManC, HudsonG, DurhamSE, et al. (2006) Mutant POLG2 Disrupts DNA Polymerase gamma Subunits and Causes Progressive External Ophthalmoplegia. Am J Hum Genet 78: 1026–1034.

12. StumpfJD, CopelandWC (2013) The exonuclease activity of the yeast mitochondrial DNA polymerase gamma suppresses mitochondrial DNA deletions between short direct repeats in Saccharomyces cerevisiae. Genetics 194: 519–522.

13. BaruffiniE, FerreroI, FouryF (2007) Mitochondrial DNA defects in Saccharomyces cerevisiae caused by functional interactions between DNA polymerase gamma mutations associated with disease in human. Biochim Biophys Acta 1772: 1225–1235.

14. BaruffiniE, LodiT, DallabonaC, PuglisiA, ZevianiM, et al. (2006) Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. Hum Mol Genet 15: 2846–2855.

15. KakudaTN (2000) Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22: 685–708.

16. StumpfJD, SanetoRP, CopelandWC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5: a011395.

17. BlackwoodW, BuxtonPH, CumingsJN, RobertsonDJ, TuckerSM (1963) Diffuse cerebral degeneration in infancy (Alpers' disease). Arch Dis Child 38: 193–204.

18. GagoMF, RosasMJ, GuimaraesJ, FerreiraM, VilarinhoL, et al. (2006) SANDO: Two novel mutations in POLG1 gene. Neuromuscul Disord 16: 507–509.

19. LeeYS, KennedyWD, YinYW (2009) Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations. Cell 139: 312–324.

20. LongleyMJ, PrasadR, SrivastavaDK, WilsonSH, CopelandWC (1998) Identification of 5′-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitro. Proc Natl Acad Sci U S A 95: 12244–12248.

21. LongleyMJ, RoppPA, LimSE, CopelandWC (1998) Characterization of the native and recombinant catalytic subunit of human DNA polymerase gamma: identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity. Biochemistry 37: 10529–10539.

22. JohnsonAA, JohnsonKA (2001) Exonuclease proofreading by human mitochondrial dna polymerase. J Biol Chem 276: 38097–38107.

23. ChanSS, NaviauxRK, BasingerAA, CasasKA, CopelandWC (2009) De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome. Mitochondrion 9: 340–345.

24. KasiviswanathanR, LongleyMJ, ChanSS, CopelandWC (2009) Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in MtDNA replication. J Biol Chem 284: 19501–19510.

25. PonamarevMV, LongleyMJ, NguyenD, KunkelTA, CopelandWC (2002) Active Site Mutation in DNA Polymerase gamma Associated with Progressive External Ophthalmoplegia Causes Error-prone DNA Synthesis. J Biol Chem 277: 15225–15228.

26. GraziewiczMA, LongleyMJ, BienstockRJ, ZevianiM, CopelandWC (2004) Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol 11: 770–776.

27. GraziewiczMA, BienstockRJ, CopelandWC (2007) The DNA polymerase {gamma} Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 7,8-dihydro-8-oxo-2′-deoxyguanosine. Hum Mol Genet 16: 2729–2739.

28. FouryF (1989) Cloning and sequencing of the nuclear gene MIP1 encoding the catalytic subunit of the yeast mitochondrial DNA polymerase. J Biol Chem 264: 20552–20560.

29. RoppPA, CopelandWC (1996) Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 36: 449–458.

30. BaruffiniE, FerreroI, FouryF (2010) In vivo analysis of mtDNA replication defects in yeast. Methods 51: 426–436.

31. FouryF, VanderstraetenS (1992) Yeast mitochondrial DNA mutators with deficient proofreading exonucleolytic activity. Embo J 11: 2717–2726.

32. VermulstM, BielasJH, KujothGC, LadigesWC, RabinovitchPS, et al. (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39: 540–543.

33. VermulstM, WanagatJ, KujothGC, BielasJH, RabinovitchPS, et al. (2008) DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40: 392–394.

34. LewisW, DayBJ, KohlerJJ, HosseiniSH, ChanSSL, et al. (2007) MtDNA depletion, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest 87: 326–335.

35. PirselM, BohrVA (1993) Methyl methanesulfonate adduct formation and repair in the DHFR gene and in mitochondrial DNA in hamster cells. Carcinogenesis 14: 2105–2108.

36. FurdaAM, MarrangoniAM, LokshinA, Van HoutenB (2012) Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction. DNA Repair (Amst) 11: 684–692.

37. Acevedo-TorresK, Fonseca-WilliamsS, Ayala-TorresS, Torres-RamosCA (2009) Requirement of the Saccharomyces cerevisiae APN1 gene for the repair of mitochondrial DNA alkylation damage. Environ Mol Mutagen 50: 317–327.

38. YouHJ, SwansonRL, HarringtonC, CorbettAH, Jinks-RobertsonS, et al. (1999) Saccharomyces cerevisiae Ntg1p and Ntg2p: broad specificity N-glycosylases for the repair of oxidative DNA damage in the nucleus and mitochondria. Biochemistry 38: 11298–11306.

39. JinYH, ClarkAB, SlebosRJ, Al-RefaiH, TaylorJA, et al. (2003) Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34: 326–329.

40. BogenhagenDF, PinzKG, Perez-JannottiRM (2001) Enzymology of mitochondrial base excision repair. Prog Nucleic Acid Res Mol Biol 68: 257–271.

41. YangY, SterlingJ, StoriciF, ResnickMA, GordeninDA (2008) Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae. PLoS Genet 4: e1000264.

42. RobertsSA, SterlingJ, ThompsonC, HarrisS, MavD, et al. (2012) Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell 46: 424–435.

43. YangY, GordeninDA, ResnickMA (2010) A single-strand specific lesion drives MMS-induced hyper-mutability at a double-strand break in yeast. DNA Repair (Amst) 9: 914–921.

44. ClaytonDA (1982) Replication of animal mitochondrial DNA. Cell 28: 693–705.

45. CopelandWC, WangTS (1993) Mutational analysis of the human DNA polymerase alpha. The most conserved region in alpha-like DNA polymerases is involved in metal- specific catalysis. J Biol Chem 268: 11028–11040.

46. KalifaL, SiaEA (2007) Analysis of Rev1p and Pol zeta in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance. DNA Repair (Amst) 6: 1732–1739.

47. VanderstraetenS, Van den BruleS, HuJ, FouryF (1998) The role of 3′-5′ exonucleolytic proofreading and mismatch repair in yeast mitochondrial DNA error avoidance. J Biol Chem 273: 23690–23697.

48. PogorzalaL, MookerjeeS, SiaEA (2009) Evidence that msh1p plays multiple roles in mitochondrial base excision repair. Genetics 182: 699–709.

49. StrandMK, StuartGR, LongleyMJ, GraziewiczMA, DominickOC, et al. (2003) POS5 gene of Saccharomyces cerevisiae encodes a mitochondrial NADH kinase required for stability of mitochondrial DNA. Eukaryot Cell 2: 809–820.

50. KalifaL, BeutnerG, PhadnisN, SheuSS, SiaEA (2009) Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity. DNA Repair (Amst) 8: 1242–1249.

51. PhadnisN, MehtaR, MeednuN, SiaEA (2006) Ntg1p, the base excision repair protein, generates mutagenic intermediates in yeast mitochondrial DNA. DNA Repair (Amst) 5: 829–839.

52. DoudicanNA, SongB, ShadelGS, DoetschPW (2005) Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. Mol Cell Biol 25: 5196–5204.

53. StumpfJD, CopelandWC (2011) Mitochondrial DNA replication and disease: insights from DNA polymerase gamma mutations. Cell Mol Life Sci 68: 219–233.

54. TranHT, KeenJD, KrickerM, ResnickMA, GordeninDA (1997) Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol Cell Biol 17: 2859–2865.

55. SorF, FukuharaH (1984) Erythromycin and spiramycin resistance mutations of yeast mitochondria: nature of the rib2 locus in the large ribosomal RNA gene. Nucleic Acids Res 12: 8313–8318.