Mitochondria pp 323-347 | Cite as

Mitochondrial DNA Damage and Repair

  • Inna N. Shokolenko
  • Susan P. Ledoux
  • Glenn L. Wilson
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 2)


One of the unique features of mitochondria is that these organelles possess their own DNA (mtDNA). The mitochondrial genome, like any DNA is subject to continuous attack on its integrity from both endogenous and exogenous sources. In order to understand the consequences of such an attack, one must consider key aspects of mtDNA organization and maintenance. Mammalian cells contain one to several thousand copies of mtDNA per cell, which are characterized as being enclosed in multiple mitochondria at 1 to 11 copies per organelle (Cavelier et al. 2000). Human mtDNA is a circular negatively supercoiled double-stranded molecule that is 16,569 bp long (Figure 15.1). It encodes 13 polypeptides, 22 tRNAs and 2 rRNAs.


Base Excision Repair Thymine Glycol Multiple Colorectal Adenoma Mitochondrial Base Excision Repair Endogenous Oxidative Damage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP (2002) Inherited variants of MYH associated with somatic G:C—T:A mutations in colorectal tumors. Nat Genet 30: 227–232PubMedGoogle Scholar
  2. Allen JA, Coombs MM Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA (1980) Nature 287: 244–245PubMedGoogle Scholar
  3. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 90: 7915–7922PubMedGoogle Scholar
  4. Anderson CT, Friedberg EC (1980) The presence of nuclear and mitochondrial uracil-DNA glycosylase in extracts of human KB cells. Nucleic Acids Res 8: 875–888PubMedGoogle Scholar
  5. Anson RM, Hudson E, Bohr VA (2000) Mitochondrial endogenous oxidative damage has been overestimated. FASEB J 14: 355–360PubMedGoogle Scholar
  6. Asagoshi K, Yamada T, Okada Y, Terato H, Ohyama Y, Seki S, Ide H (2000) Recognition of formamidopyrimidine by Escherichia coli and mammalian thymine glycol glycosylases. Distinctive paired base effects and biological and mechanistic implications. J Biol Chem 275: 24781–24786PubMedGoogle Scholar
  7. Aspinwall R, Rothwell DG, Roldan-Arjona T, Anselmino C, Ward CJ, Cheadle J P, Sampson JR, Lindahl T, Harris PC, Hickson ID (1997) Cloning and characterization of a functional human homolog of Escherichia coli endonuclease III. Proc Natl Acad Sci USA 94: 109–114PubMedGoogle Scholar
  8. Attardi G, Schatz G (1988) Biogenesis of mitochondria. Annu Rev Cell Biol 4: 289–333PubMedGoogle Scholar
  9. Backer JM, Weinstein IB (1980) Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo[a]pyrene. Science 209: 297–299PubMedGoogle Scholar
  10. Beckman KB, Ames BN (1999) Endogenous oxidative damage of mtDNA. Mutat Res 424: 51–58PubMedGoogle Scholar
  11. Bjelland S, Seeberg E (2003) Mutagenicity, toxicity and repair of DNA base damage induced by oxidation. Mutat Res 531: 37–80PubMedGoogle Scholar
  12. Bogenhagen DF, Pinz KG, Perez-Jannotti RM (2001) Enzymology of mitochondrial base excision repair. Prog Nucleic Acid Res Mol Biol 68: 257–271PubMedGoogle Scholar
  13. Bogenhagen DF, Wang Y, Shen EL, Kobayashi R (2003) Protein components of mitochondrial DNA nucleoids in higher eukaryotes. Mol Cell Proteomics 2: 1205–1216PubMedGoogle Scholar
  14. Bohr VA, Stevnsner T, de Souza-Pinto NC (2002) Mitochondrial DNA repair of oxidative damage in mammalian cells. Gene 286: 127–134PubMedGoogle Scholar
  15. Boiteux S, Radicella JP (2000) The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Arch Biochem Biophys 377: 1–8PubMedGoogle Scholar
  16. Brown WM, George M Jr, Wilson AC (1979) Rapid evolution of animal mitochondrial DNA. Proc Natl Acad Sci USA 76: 1967–1971PubMedGoogle Scholar
  17. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29: 222–230PubMedGoogle Scholar
  18. Cadet J, Delatour T, Douki T, Gasparutto D, Pouget JP, Ravanat JL, Sauvaigo S (1999) Hydroxyl radicals and DNA base damage. Mutat Res 424: 9–21PubMedGoogle Scholar
  19. Cavelier L, Johannisson A, Gyllensten U (2000) Analysis of mtDNA copy number and composition of single mitochondrial particles using flow cytometry and PCR. Exp Cell Res 259: 79–85PubMedGoogle Scholar
  20. Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA (1992) 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G—-T and A—-C substitutions. J Biol Chem 267: 166–172PubMedGoogle Scholar
  21. Christmann M, Tomicic MT, Roos WP, Kaina B (2003) Mechanisms of human DNA repair: an update. Toxicology 193: 3–34PubMedGoogle Scholar
  22. Clayton DA, Doda JN, Friedberg EC (1974) The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci USA 71: 2777–2781PubMedGoogle Scholar
  23. Collins AR, Cadet J, Moller L, Poulsen HE, Vina J (2004) Are we sure we know how to measure 8-oxo-7,8-dihydroguanine in DNA from human cells? Arch Biochem Biophys 423: 57–65PubMedGoogle Scholar
  24. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17: 1195–1214PubMedGoogle Scholar
  25. Copeland WC, Longley MJ (2003) DNA polymerase gamma in mitochondrial DNA replication and repair. Scientific World Journal 3: 34–44PubMedGoogle Scholar
  26. Copeland WC, Wachsman JT, Johnson FM, Penta JS (2002) Mitochondrial DNA alterations in cancer. Cancer Invest 20: 557–569PubMedGoogle Scholar
  27. Croteau DL, Stierum RH, Bohr VA (1999) Mitochondrial DNA repair pathways. Mutat Res 434: 137–148PubMedGoogle Scholar
  28. de Souza-Pinto NC, Eide L, Hogue BA, Thybo T, Stevnsner T, Seeberg E, Klungland A, Bohr VA (2001) Repair of 8-oxodeoxyguanosine lesions in mitochondrial dna depends on the oxoguanine DNA glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial dna of OGG1-defective mice. Cancer Res 61: 5378–5381PubMedGoogle Scholar
  29. DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348: 2656–2668PubMedGoogle Scholar
  30. Dizdaroglu M (2005) Base-excision repair of oxidative DNA damage by DNA glycosylases. Mutat Res 591:45–59PubMedGoogle Scholar
  31. Dizdaroglu M (1998) Mechanisms of free radical damage to DNA. In: O. I. H. Aruoma (ed.), DNA & Free Radicals: Techniques, Mechanisms & Applications, pp. 3–26. Saint Lucia: OICA InternationalGoogle Scholar
  32. Dobson AW, Grishko V, LeDoux SP, Kelley MR, Wilson GL, Gillespie MN (2002) Enhanced mtDNA repair capacity protects pulmonary artery endothelial cells from oxidant-mediated death. Am J Physiol Lung Cell Mol Physiol 283: L205–210PubMedGoogle Scholar
  33. Dobson AW, Xu Y, Kelley MR, LeDoux SP, Wilson GL (2000) Enhanced mitochondrial DNA repair and cellular survival after oxidative stress by targeting the human 8-oxoguanine glycosylase repair enzyme to mitochondria. J Biol Chem 275: 37518–37523PubMedGoogle Scholar
  34. Doroshow JH, Davies KJ (1986) Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem 261: 3068–3074PubMedGoogle Scholar
  35. Driggers WJ, LeDoux SP, Wilson GL (1993) Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells. J Biol Chem 268: 22042–22045PubMedGoogle Scholar
  36. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95PubMedGoogle Scholar
  37. Druzhyna NM, Hollensworth SB, Kelley MR, Wilson GL, Ledoux SP (2003) Targeting human 8-oxoguanine glycosylase to mitochondria of oligodendrocytes protects against menadione-induced oxidative stress. Glia 42: 370–378PubMedGoogle Scholar
  38. Durham SE, Krishnan KJ, Betts J, Birch-Machin MA (2003) Mitochondrial DNA damage in non-melanoma skin cancer. Br J Cancer 88: 90–95PubMedGoogle Scholar
  39. ESCODD (2002) Comparative analysis of baseline 8-oxo-7,8-dihydroguanine in mammalian cell DNA, by different methods in different laboratories: an approach to consensus. Carcinogenesis 23: 2129–2133Google Scholar
  40. ESCODD (2003) Measurement of DNA oxidation in human cells by chromatographic and enzymic methods. Free Radic Biol Med 34: 1089–1099Google Scholar
  41. Fishel ML, Seo YR, Smith ML, Kelley MR (2003) Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing. Cancer Res 63: 608615PubMedGoogle Scholar
  42. Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, Sidransky D (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287: 2017–2019PubMedGoogle Scholar
  43. Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN (2003) Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell 14: 1583–1596PubMedGoogle Scholar
  44. Geromel V, Kadhom N, Cebalos-Picot I, Ouari O, Polidori A, Munnich A, Rotig A, Rustin P (2001) Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum Mol Genet 10: 1221–1228PubMedGoogle Scholar
  45. Graziewicz MA, Day BJ, Copeland WC (2002) The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res 30: 2817–2824PubMedGoogle Scholar
  46. Grollman AP, Moriya M (1993) Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet 9: 246–249PubMedGoogle Scholar
  47. Gross NJ, Getz GS, Rabinowitz M (1969) Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J Biol Chem 244: 1552–1562PubMedGoogle Scholar
  48. Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson AA (2001) Reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. Nucleic Acids Res 29: 2117–2126PubMedGoogle Scholar
  49. Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA, Yeo, HC, Ames BN (1998) DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci USA 95: 288-293PubMedGoogle Scholar
  50. Hilbert TP, Chaung W, Boorstein RJ, Cunningham RP, Teebor GW (1997) Cloning and expression of the cDNA encoding the human homologue of the DNA repair enzyme, Escherichia coli endonuclease III. J Biol Chem 272: 6733–6740PubMedGoogle Scholar
  51. Hollensworth SB, Shen C, Sim JE, Spitz DR, Wilson GL, LeDoux SP (2000) Glial cell type-specific responses to menadione-induced oxidative stress. Free Radic Biol Med 28: 1161–1174PubMedGoogle Scholar
  52. Holt IJ, Harding AE, Morgan-Hughes JA (1998) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717–719Google Scholar
  53. Ikeda S, Biswas T, Roy R, Izumi T, Boldogh I, Kurosky A, Sarker AH, Seki S, Mitra S (1998) Purification and characterization of human NTH1, a homolog of Escherichia coli endonuclease III. Direct identification of Lys-212 as the active nucleophilic residue. J Biol Chem 273: 21585–21593PubMedGoogle Scholar
  54. Jones S, Emmerson P, Maynard J, Best JM, Jordan S, Williams GT, Sampson JR, Cheadle JP (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C–>T:A mutations. Hum Mol Genet 11: 2961–2967PubMedGoogle Scholar
  55. Kaguni LS (2004) DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 73: 293–320PubMedGoogle Scholar
  56. Kang D, Hamasaki N (2005) Alterations of mitochondrial DNA in common diseases and disease states: aging, neurodegeneration, heart failure, diabetes, and cancer. Curr Med Chem 12: 429–441PubMedGoogle Scholar
  57. Kang D, Nishida J, Iyama A, Nakabeppu Y, Furuichi M, Fujiwara T, Sekiguchi M, Takeshige K (1995) Intracellular localization of 8-oxo-dGTPase in human cells, with special reference to the role of the enzyme in mitochondria. J Biol Chem 270: 14659–14665PubMedGoogle Scholar
  58. Karahalil B, de Souza-Pinto NC, Parsons JL, Elder RH, Bohr VA (2003) Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases. J Biol Chem 278: 33701–33707PubMedGoogle Scholar
  59. Khrapko K, Coller HA, Andre PC, Li XC, Hanekamp JS, Thilly WG (1997) Mitochondrial mutational spectra in human cells and tissues. Proc Natl Acad Sci USA 94: 13798–13803PubMedGoogle Scholar
  60. Klein JC, Bleeker MJ, Saris CP, Roelen HC, Brugghe HF, van den Elst H, van der Marel GA, van Boom JH, Westra JG, Kriek E, Berens AJM (1992) Repair and replication of plasmids with site-specific 8-oxodG and 8-AAFdG residues in normal and repair-deficient human cells. Nucleic Acids Res 20: 4437–4443PubMedGoogle Scholar
  61. Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, Seeberg E, Lindahl T, Barnes DE (1999) Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 96: 13300–13305PubMedGoogle Scholar
  62. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M (2004) Reconstitution of a minimal mtDNA replisome in vitro. Embo J 23: 2423–2429PubMedGoogle Scholar
  63. Krokan HE, Otterlei M, Nilsen H, Kavli B, Skorpen F, Andersen S, Skjelbred C, Akbari M, Aas PA, Slupphaug G (2001) Properties and functions of human uracil-DNA glycosylase from the UNG gene. Prog Nucleic Acid Res Mol Biol 68: 365–386PubMedGoogle Scholar
  64. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481–484PubMedGoogle Scholar
  65. Kunishige M, Mitsui T, Akaike M, Kawajiri M, Shono M, Kawai H, Matsumoto T (2003) Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy. Muscle Nerve 28: 484–492PubMedGoogle Scholar
  66. Lakshmipathy U, Campbell C (2001) Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity. Nucleic Acids Res 29: 668–676PubMedGoogle Scholar
  67. Lakshmipathy U, Campbell C (2000) Mitochondrial DNA ligase III function is independent of Xrcc1. Nucleic Acids Res 28: 3880–3886PubMedGoogle Scholar
  68. Lakshmipathy U, Campbell C (1999) The human DNA ligase III gene encodes nuclear and mitochondrial proteins. Mol Cell Biol 19: 3869–3876PubMedGoogle Scholar
  69. Le Page F, Margot A, Grollman AP, Sarasin A, Gentil A (1995) Mutagenicity of a unique 8-oxoguanine in a human Ha-ras sequence in mammalian cells. Carcinogenesis 16: 2779–2784PubMedGoogle Scholar
  70. LeDoux SP, Driggers WJ, Hollensworth BS, Wilson GL (1999) Repair of alkylation and oxidative damage in mitochondrial DNA. Mutat Res 434: 149–159PubMedGoogle Scholar
  71. Ledoux SP, Shen CC, Grishko VI, Fields PA, Gard AL, Wilson GL (1998) Glial cell-specific differences in response to alkylation damage. Glia 24: 304–312PubMedGoogle Scholar
  72. LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K, Bohr VA (1992) Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis 13: 1967–1973PubMedGoogle Scholar
  73. Legros F, Malka F, Frachon P, Lombes A, Rojo M (2004) Organization and dynamics of human mitochondrial DNA. J Cell Sci 117: 2653–2662PubMedGoogle Scholar
  74. Lestienne P, Ponsot G (1988) Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. Lancet 1: 885PubMedGoogle Scholar
  75. Lim KS, Jeyaseelan K, Whiteman M, Jenner A, Halliwell B (2005) Oxidative damage in mitochondrial DNA is not extensive. Ann N Y Acad Sci 1042: 210–220PubMedGoogle Scholar
  76. Longley MJ, Prasad R, Srivastava DK, Wilson SH, Copeland WC (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 USA 95: 12244–12248PubMedGoogle Scholar
  77. Lu CY, Wang EK, Lee HC, Tsay HJ, Wei YH (2003) Increased expression of manganese-superoxide dismutase in fibroblasts of patients with CPEO syndrome. Mol Genet Metab 80: 321–329PubMedGoogle Scholar
  78. Lu R, Nash HM, Verdine GLA (1997) Mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancer. Curr Biol 7: 397–407PubMedGoogle Scholar
  79. Luna L, Bjoras M, Hoff E, Rognes T, Seeberg E (2000) Cell-cycle regulation, intracellular sorting and induced overexpression of the human NTH1 DNA glycosylase involved in removal of formamidopyrimidine residues from DNA. Mutat Res 460: 95–104PubMedGoogle Scholar
  80. Magana-Schwencke N, Henriques J A, Chanet R, Moustacchi E The fate of 8-methoxypsoralen photoinduced crosslinks in nuclear and mitochondrial yeast DNA: comparison of wild-type and repair-deficient strains. Proc Natl Acad Sci U S A 79: 1722–1726, 1982PubMedGoogle Scholar
  81. Mambo E, Gao X, Cohen Y, Guo Z, Talalay P, Sidransky D (2003) Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc Natl Acad Sci USA 100: 1838-1843PubMedGoogle Scholar
  82. Martinez GR, Loureiro AP, Marques SA, Miyamoto S, Yamaguchi LF, Onuki J, Almeida EA, Garcia CC, Barbosa LF, Medeiros MH, Di Mascio P (2003) Oxidative and alkylating damage in DNA. Mutat Res 544: 115–127PubMedGoogle Scholar
  83. Miyaki M, Yatagai K, Ono T (1977) Strand breaks of mammalian mitochondrial DNA induced by carcinogens. Chem Biol Interact 17: 321–329PubMedGoogle Scholar
  84. Moriya M (1993) Single-stranded shuttle phagemid for mutagenesis studies in mammalian cells: 8-oxoguanine in DNA induces targeted G.C–>T.A transversions in simian kidney cells. Proc Natl Acad Sci USA 90: 1122-1126PubMedGoogle Scholar
  85. Moriya M, Ou C, Bodepudi V, Johnson F, Takeshita M, Grollman AP (1991) Site-specific mutagenesis using a gapped duplex vector: a study of translesion synthesis past 8-oxodeoxyguanosine in E. coli. Mutat Res 254: 281–288Google Scholar
  86. Nakabeppu Y (2001) Molecular genetics and structural biology of human MutT homolog, MTH1. Mutat Res 477: 59–70PubMedGoogle Scholar
  87. Nakabeppu Y (2001) Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Prog Nucleic Acid Res Mol Biol 68: 75–94PubMedGoogle Scholar
  88. Nakabeppu Y, Tsuchimoto D, Ichinoe A, Ohno M, Ide Y, Hirano S, Yoshimura D, Tominaga Y, Furuichi M, Sakumi K (2004) Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: from mitochondria to nuclei. Ann N Y Acad Sci 1011: 101–111PubMedGoogle Scholar
  89. Neubert D, Hopfenmuller W, Fuchs G (1981) Manifestation of carcinogenesis as a stochastic process on the basis of an altered mitochondrial genome. Arch Toxicol 48: 89–125PubMedGoogle Scholar
  90. Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, Daly G, Krokan HE, Lindahl T, Barnes DE (2000) Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication. Mol Cell 5: 1059–1065PubMedGoogle Scholar
  91. Niranjan BG, Bhat NK, Avadhani NG (1982) Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science 215: 73–75PubMedGoogle Scholar
  92. Nishioka K, Ohtsubo T, Oda H, Fujiwara T, Kang D, Sugimachi K, Nakabeppu Y (1999) Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs. Mol Biol Cell 10: 1637–1652PubMedGoogle Scholar
  93. Ocampo MT, Chaung W, Marenstein DR, Chan MK, Altamirano A, Basu AK, Boorstein RJ, Cunningham RP, Teebor GW (2002) Targeted deletion of mNth1 reveals a novel DNA repair enzyme activity. Mol Cell Biol 22: 6111-6121PubMedGoogle Scholar
  94. Ohtsubo T, Nishioka K, Imaiso Y, Iwai S, Shimokawa H, Oda H, Fujiwara T, Nakabeppu Y (2000) Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucleic Acids Res 28: 1355–1364PubMedGoogle Scholar
  95. Parker A, Gu Y, Lu AL (2000) Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria. Nucleic Acids Res 28: 3206–3215PubMedGoogle Scholar
  96. Pavlov YI, Minnick DT, Izuta S, Kunkel TA (1994) DNA replication fidelity with 8-oxodeoxyguanosine triphosphate. Biochemistry 33: 4695–4701PubMedGoogle Scholar
  97. Pelicano H, Carney D, Huang P (2004) ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 7: 97–110PubMedGoogle Scholar
  98. Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102: 719–724PubMedGoogle Scholar
  99. Pettepher CC, LeDoux SP, Bohr VA, Wilson GL (1991) Repair of alkali-labile sites within the mitochondrial DNA of RINr 38 cells after exposure to the nitrosourea streptozotocin. J Biol Chem 266: 3113–3117PubMedGoogle Scholar
  100. Pinz KG, Bogenhagen DF (2000) Characterization of a catalytically slow AP lyase activity in DNA polymerase gamma and other family A DNA polymerases. J Biol Chem 275: 12509–12514PubMedGoogle Scholar
  101. Pinz KG, Bogenhagen DF (1998) Efficient repair of abasic sites in DNA by mitochondrial enzymes. Mol Cell Biol 18: 1257–1265PubMedGoogle Scholar
  102. Pinz KG, Shibutani S, Bogenhagen DF (1995) Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. J Biol Chem 270: 9202–9206PubMedGoogle Scholar
  103. Pirsel M, Bohr VA (1993) Methyl methanesulfonate adduct formation and repair in the DHFR gene and in mitochondrial DNA in hamster cells. Carcinogenesis 14: 2105–2108PubMedGoogle Scholar
  104. Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20: 291–293PubMedGoogle Scholar
  105. Rachek LI, Grishko VI, Alexeyev MF, Pastukh VV, LeDoux SP, Wilson, GL (2004) Endonuclease III and endonuclease VIII conditionally targeted into mitochondria enhance mitochondrial DNA repair and cell survival following oxidative stress. Nucleic Acids Res 32: 3240–3247PubMedGoogle Scholar
  106. Rachek LI, Grishko VI, Musiyenko SI, Kelley MR, LeDoux SP, Wilson GL (2002) Conditional targeting of the DNA repair enzyme hOGG1 into mitochondria. J Biol Chem 277: 44932–44937PubMedGoogle Scholar
  107. Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25: 502–508PubMedGoogle Scholar
  108. Richter C, Park JW, Ames BN (1998) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 85: 6465–6467Google Scholar
  109. Rossi SC, Gorman N, Wetterhahn KE (1988) Mitochondrial reduction of the carcinogen chromate: formation of chromium(V). Chem Res Toxicol 1: 101–107PubMedGoogle Scholar
  110. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73: 39–85PubMedGoogle Scholar
  111. Sawyer DE, Van Houten B (1999) Repair of DNA damage in mitochondria. Mutat Res 434: 161–176PubMedGoogle Scholar
  112. Scharer OD (2003) Chemistry and biology of DNA repair. Angew Chem Int Ed Engl 42: 2946–2974PubMedGoogle Scholar
  113. Senturker S, Dizdaroglu M (1999) The effect of experimental conditions on the levels of oxidatively modified bases in DNA as measured by gas chromatography-mass spectrometry: how many modified bases are involved? Prepurification or not? Free Radic Biol Med 27: 370–380PubMedGoogle Scholar
  114. Shadel GS, Clayton DA (1997) Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem 66: 409–435PubMedGoogle Scholar
  115. Shokolenko IN, Alexeyev MF, LeDoux SP, Wilson GL (2005) TAT-mediated protein transduction and targeted delivery of fusion proteins into mitochondria of breast cancer cells. DNA Repair (Amst) 4: 511–518Google Scholar
  116. Shokolenko IN, Alexeyev MF, Robertson FM, LeDoux SP, Wilson GL (2003) The expression of Exonuclease III from E. coli in mitochondria of breast cancer cells diminishes mitochondrial DNA repair capacity and cell survival after oxidative stress. DNA Repair (Amst) 2: 471–482Google Scholar
  117. Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348: 791–799PubMedGoogle Scholar
  118. Singer TP, Ramsay RR (1990) Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett 274: 1–8PubMedGoogle Scholar
  119. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24: 7779–7788PubMedGoogle Scholar
  120. Steenken S (1997) Electron transfer in DNA? Competition by ultra-fast proton transfer? Biol Chem 378: 1293–1297PubMedGoogle Scholar
  121. Stierum RH, Dianov GL, Bohr VA (1999) Single-nucleotide patch base excision repair of uracil in DNA by mitochondrial protein extracts. Nucleic Acids Res 27: 3712–3719PubMedGoogle Scholar
  122. Szczesny B, Hazra TK, Papaconstantinou J, Mitra S, Boldogh I (2003) Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci USA 100: 10670–10675PubMedGoogle Scholar
  123. Taanman JW (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410: 103–123PubMedGoogle Scholar
  124. Takao M, Aburatani H, Kobayashi K, Yasui A (1998) Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Nucleic Acids Res 26: 2917–2922PubMedGoogle Scholar
  125. Takao M, Kanno S, Shiromoto T, Hasegawa R, Ide H, Ikeda S, Sarker AH, Seki S, Xing JZ, Le XC, Weinfeld M, Kobayashi K, Miyazaki J, Muijtjens M, Hoeijmakers JH, van der Horst G, Yasui A (2002) Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols. Embo J 21: 3486–3493PubMedGoogle Scholar
  126. Takayama S, Muramatsu M (1969) Incorporation of tritiated dimethylnitrosamine into subcellular fractions of mouse liver after long term administration of dimethylnitrosamine. Z Krebsforsch 73: 172–179PubMedGoogle Scholar
  127. Tomasi A, Albano E, Banni S, Botti B, Corongiu F, Dessi MA, Iannone A, Vannini V, Dianzani MU (1987) Free-radical metabolism of carbon tetrachloride in rat liver mitochondria. A study of the mechanism of activation. Biochem J 246: 313–317PubMedGoogle Scholar
  128. Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci 24: 7771–7778PubMedGoogle Scholar
  129. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom, R, Tornell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423PubMedGoogle Scholar
  130. Tsuzuki T, Egashira A, Igarashi H, Iwakuma T, Nakatsuru Y, Tominaga Y, Kawate H, Nakao K, Nakamura K, Ide F, Kura S, Nakabeppu Y, Katsuki M, Ishikawa T, Sekiguchi M (2001) Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proc Natl Acad Sci USA 98: 11456–11461PubMedGoogle Scholar
  131. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16: 29–37PubMedGoogle Scholar
  132. Wadia JS, Dowdy SF (2005) Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. Adv Drug Deliv Rev 57: 579–596PubMedGoogle Scholar
  133. Wallace DCA (2005) Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine. Annu Rev Genet 39:359–407PubMedGoogle Scholar
  134. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ (1988) 2nd, Nikoskelainen E K Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242: 1427–1430PubMedGoogle Scholar
  135. Wallace SS (1998) Enzymatic processing of radiation-induced free radical damage in DNA. Radiat Res 150: S60–79PubMedGoogle Scholar
  136. Wood ML, Dizdaroglu M, Gajewski E, Essigmann JM (1990) Mechanistic studies of ionizing radiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. Biochemistry 29: 7024–7032PubMedGoogle Scholar
  137. Wunderlich V, Schutt M, Bottger M, Graffi A (1970) Preferential alkylation of mitochondrial deoxyribonucleic acid by N-methyl-N-nitrosourea. Biochem J 118: 99–109PubMedGoogle Scholar
  138. Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 94: 514–519PubMedGoogle Scholar
  139. Yakubovskaya E, Chen Z, Carrodeguas JA, Kisker C, Bogenhagen DF (2006) Functional human mitochondrial DNA polymerase gamma forms a heterotrimer. J Biol Chem 281: 374–382PubMedGoogle Scholar
  140. Yang MY, Bowmaker M, Reyes A, Vergani L, Angeli P, Gringeri E, Jacobs H T, Holt IJ (2002) Biased incorporation of ribonucleotides on the mitochondrial L-strand accounts for apparent strand-asymmetric DNA replication. Cell 111: 495–505PubMedGoogle Scholar
  141. Yoneda M, Katsumata K, Hayakawa M, Tanaka M, Ozawa T (1995) Oxygen stress induces an apoptotic cell death associated with fragmentation of mitochondrial genome. Biochem Biophys Res Commun 209: 723–729PubMedGoogle Scholar
  142. Zastawny TH, Dabrowska M, Jaskolski T, Klimarczyk M, Kulinski L, Koszela A, Szczesniewicz M, Sliwinska M, Witkowski P, Olinski R (1998) Comparison of oxidative base damage in mitochondrial and nuclear DNA. Free Radic Biol Med 24: 722–725PubMedGoogle Scholar
  143. Zhang D, Mott JL, Farrar P, Ryerse JS, Chang SW, Stevens M, Denniger G, Zassenhaus HP (2003) Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy. Cardiovasc Res 57: 147–157PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Inna N. Shokolenko
  • Susan P. Ledoux
  • Glenn L. Wilson

There are no affiliations available

Personalised recommendations