Biopolym. Cell. 2016; 32(4):245-261.
Reviews
Mechanisms of DNA repair in mitochondria
1Singatulina A. S., 1Pestryakov P. E.
  1. Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
    8, Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

Abstract

The role of mitochondria in cellular metabolism and functioning can hardly be overestimated. Mitochondria carry out many functions, and their main function is the production of ATP, the energetic “currency” of the cell. Mitochondria possess a small circular DNA, which codes for 13 proteins. Mitochondrial DNA, or mtDNA, as well as the nuclear one, is subjected to the influence of environmental and endogenous factors. This may lead to mtDNA damage. Here we review the data on mtDNA damage and repair mechanisms. The functioning of mitochondria directly depends on integrity of mtDNA, and therefore, on correct functioning of the mtDNA repair system. These systems differ from the repair systems of nuclear DNA and are in general understudied. The existence of excision nucleotides repair system correcting bulky lesions in mitochondria is still under question. Secific degradation of damaged mtDNA can probably serve as an alternative way to prevent the accumulation of bulky lesions. A search for new pathways of mtDNA repair is of considerable interest
Keywords: Mitochondrial DNA, mtDNA repair system, mtDNA damages

References

[1] Dyall SD, Brown MT, Johnson PJ. Ancient invasions: from endosymbionts to organelles. Science. 2004;304(5668):253-7.
[2] Gupta S. Molecular steps of death receptor and mitochondrial pathways of apoptosis. Life Sci. 2001;69(25-26):2957-64.
[3] Hsu TC, Young MR, Cmarik J, Colburn NH. Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis. Free Radic Biol Med. 2000;28(9):1338-48.
[4] Bauer MF, Gempel K, Hofmann S, Jaksch M, Philbrook C, Gerbitz KD. Mitochondrial disorders. A diagnostic challenge in clinical chemistry. Clin Chem Lab Med. 1999;37(9):855-76.
[5] Han D, Dara L, Win S, Than TA, Yuan L, Abbasi SQ, Liu ZX, Kaplowitz N. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci. 2013;34(4):243-53.
[6] Druzhyna NM, Wilson GL, LeDoux SP. Mitochondrial DNA repair in aging and disease. Mech Ageing Dev. 2008;129(7-8):383-90.
[7] Muftuoglu M, Mori MP, de Souza-Pinto NC. Formation and repair of oxidative damage in the mitochondrial DNA. Mitochondrion. 2014;17:164-81.
[8] Mason PA, Matheson EC, Hall AG, Lightowlers RN. Mismatch repair activity in mammalian mitochondria. Nucleic Acids Res. 2003;31(3):1052-8.
[9] de Souza-Pinto NC, Mason PA, Hashiguchi K, Weissman L, Tian J, Guay D, Lebel M, Stevnsner TV, Rasmussen LJ, Bohr VA. Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst). 2009;8(6):704-19.
[10] Liu P, Demple B. DNA repair in mammalian mitochondria: Much more than we thought? Environ Mol Mutagen. 2010;51(5):417-26.
[11] D'Aurelio M, Gajewski CD, Lin MT, Mauck WM, Shao LZ, Lenaz G, Moraes CT, Manfredi G. Heterologous mitochondrial DNA recombination in human cells. Hum Mol Genet. 2004;13(24):3171-9.
[12] Kraytsberg Y, Schwartz M, Brown TA, Ebralidse K, Kunz WS, Clayton DA, Vissing J, Khrapko K. Recombination of human mitochondrial DNA. Science. 2004;304(5673):981.
[13] Bellance N, Lestienne P, Rossignol R. Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis. Front Biosci (Landmark Ed). 2009;14:4015-34.
[14] Shokolenko IN, Alexeyev MF. Mitochondrial DNA: A disposable genome? Biochim Biophys Acta. 2015;1852(9):1805-9.
[15] Basu S, Bremer E, Zhou C, Bogenhagen DF. MiGenes: a searchable interspecies database of mitochondrial proteins curated using gene ontology annotation. Bioinformatics. 2006;22(4):485-92.
[16] Holt IJ, Reyes A. Human mitochondrial DNA replication. Cold Spring Harb Perspect Biol. 2012;4(12). pii: a012971.
[17] Holt IJ, Jacobs HT. Unique features of DNA replication in mitochondria: a functional and evolutionary perspective. Bioessays. 2014;36(11):1024-31.
[18] Kukat C, Wurm CA, Spåhr H, Falkenberg M, Larsson NG, Jakobs S. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc Natl Acad Sci U S A. 2011;108(33):13534-9.
[19] Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011;18(11):1290-6.
[20] Rubio-Cosials A, Sidow JF, Jiménez-Menéndez N, Fernández-Millán P, Montoya J, Jacobs HT, Coll M, Bernadó P, Solà M. Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nat Struct Mol Biol. 2011;18(11):1281-9.
[21] Wang Y, Bogenhagen DF. Human mitochondrial DNA nucleoids are linked to protein folding machinery and metabolic enzymes at the mitochondrial inner membrane. J Biol Chem. 2006;281(35):25791-802.
[22] Singh B, Li X, Owens KM, Vanniarajan A, Liang P, Singh KK. Human REV3 DNA Polymerase Zeta Localizes to Mitochondria and Protects the Mitochondrial Genome. PLoS One. 2015;10(10):e0140409.
[23] Makarova AV, Burgers PM. Eukaryotic DNA polymerase ζ. DNA Repair (Amst). 2015;29:47-55.
[24] Figge MT, Reichert AS, Meyer-Hermann M, Osiewacz HD. Deceleration of fusion-fission cycles improves mitochondrial quality control during aging. PLoS Comput Biol. 2012;8(6):e1002576.
[25] Greaves LC, Taylor RW. Mitochondrial DNA mutations in human disease. IUBMB Life. 2006;58(3):143-51.
[26] Gilkerson RW. Mitochondrial DNA nucleoids determine mitochondrial genetics and dysfunction. Int J Biochem Cell Biol. 2009;41(10):1899-906.
[27] Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC. Classification of European mtDNAs from an analysis of three European populations. Genetics. 1996;144(4):1835-50.
[28] Chinnery PF, Hudson G. Mitochondrial genetics. Br Med Bull. 2013;106:135-59.
[29] Zapico SC, Ubelaker DH. mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences. Aging Dis. 2013;4(6):364-80.
[30] Indo HP, Yen HC, Nakanishi I, Matsumoto K, Tamura M, Nagano Y, Matsui H, Gusev O, Cornette R, Okuda T, Minamiyama Y, Ichikawa H, Suenaga S, Oki M, Sato T, Ozawa T, Clair DK, Majima HJ. A mitochondrial superoxide theory for oxidative stress diseases and aging. J Clin Biochem Nutr. 2015;56(1):1-7.
[31] Ziegler DV, Wiley CD, Velarde MC. Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell. 2015;14(1):1-7.
[32] Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan. 2014;3:6.
[33] Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002;227(9):671-82.
[34] Boesch P, Weber-Lotfi F, Ibrahim N, Tarasenko V, Cosset A, Paulus F, Lightowlers RN, Dietrich A. DNA repair in organelles: Pathways, organization, regulation, relevance in disease and aging. Biochim Biophys Acta. 2011;1813(1):186-200.
[35] Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE. Mitochondria and reactive oxygen species. Free Radic Biol Med. 2009;47(4):333-43.
[36] Zhong H, Yin H. Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol. 2015;4:193-9.
[37] Gaziev AI. [Pathways for maintenance of mitochondrial DNA integrity and mitochondrial functions in cells exposed to ionizing radiation]. Radiats Biol Radioecol. 2013;53(2):117-36.
[38] Daiber A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta. 2010;1797(6-7):897-906.
[39] Csordás G, Hajnóczky G. SR/ER-mitochondrial local communication: calcium and ROS. Biochim Biophys Acta. 2009;1787(11):1352-62.
[40] Nazarewicz RR, Dikalov SI. Mitochondrial ROS in the prohypertensive immune response. Am J Physiol Regul Integr Comp Physiol. 2013;305(2):R98-100.
[41] Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development. 2014;141(22):4206-18.
[42] Labunskyy VM, Gladyshev VN. Role of reactive oxygen species-mediated signaling in aging. Antioxid Redox Signal. 2013;19(12):1362-72.
[43] Wagner S, Rokita AG, Anderson ME, Maier LS. Redox regulation of sodium and calcium handling. Antioxid Redox Signal. 2013;18(9):1063-77.
[44] Nakamura J, Swenberg JA. Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res. 1999;59(11):2522-6.
[45] Kasiviswanathan R, Collins TR, Copeland WC. The interface of transcription and DNA replication in the mitochondria. Biochim Biophys Acta. 2012;1819(9-10):970-8.
[46] Kasiviswanathan R, Gustafson MA, Copeland WC, Meyer JN. Human mitochondrial DNA polymerase γ exhibits potential for bypass and mutagenesis at UV-induced cyclobutane thymine dimers. J Biol Chem. 2012;287(12):9222-9.
[47] Nakanishi N, Fukuoh A, Kang D, Iwai S, Kuraoka I. Effects of DNA lesions on the transcription reaction of mitochondrial RNA polymerase: implications for bypass RNA synthesis on oxidative DNA lesions. Mutagenesis. 2013;28(1):117-23.
[48] Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A. 1988;85(8):2706-8.
[49] Bjelland S, Eide L, Time RW, Stote R, Eftedal I, Volden G, Seeberg E. Oxidation of thymine to 5-formyluracil in DNA: mechanisms of formation, structural implications, and base excision by human cell free extracts. Biochemistry. 1995;34(45):14758-64.
[50] Kobashigawa S, Kashino G, Suzuki K, Yamashita S, Mori H. Ionizing radiation-induced cell death is partly caused by increase of mitochondrial reactive oxygen species in normal human fibroblast cells. Radiat Res. 2015;183(4):455-64.
[51] Cline SD. Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim Biophys Acta. 2012;1819(9-10):979-91.
[52] Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, Starr TB. Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci. 2011;120 Suppl 1:S130-45.
[53] Matsuda T, Yabushita H, Kanaly RA, Shibutani S, Yokoyama A. Increased DNA damage in ALDH2-deficient alcoholics. Chem Res Toxicol. 2006;19(10):1374-8.
[54] Yu HS, Oyama T, Isse T, Kitagawa K, Pham TT, Tanaka M, Kawamoto T. Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem Biol Interact. 2010;188(3):367-75.
[55] Backer JM, Weinstein IB. Interaction of benzo(a)pyrene and its dihydrodiol-epoxide derivative with nuclear and mitochondrial DNA in C3H10T 1/2 cell cultures. Cancer Res. 1982;42(7):2764-9.
[56] Khan QA, Kohlhagen G, Marshall R, Austin CA, Kalena GP, Kroth H, Sayer JM, Jerina DM, Pommier Y. Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: implications for interactions with intercalating anticancer agents. Proc Natl Acad Sci U S A. 2003;100(21):12498-503.
[57] Schlezinger JJ, White RD, Stegeman JJ. Oxidative inactivation of cytochrome P-450 1A (CYP1A) stimulated by 3,3',4,4'-tetrachlorobiphenyl: production of reactive oxygen by vertebrate CYP1As. Mol Pharmacol. 1999;56(3):588-97.
[58] Biswas G, Srinivasan S, Anandatheerthavarada HK, Avadhani NG. Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling. Proc Natl Acad Sci U S A. 2008;105(1):186-91.
[59] Dedon PC, Goldberg IH. Free-radical mechanisms involved in the formation of sequence-dependent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin. Chem Res Toxicol. 1992;5(3):311-32.
[60] Ang WH, Myint M, Lippard SJ. Transcription inhibition by platinum-DNA cross-links in live mammalian cells. J Am Chem Soc. 2010;132(21):7429-35.
[61] Todd RC, Lippard SJ. Inhibition of transcription by platinum antitumor compounds. Metallomics. 2009;1(4):280-91.
[62] Georgakilas AG, O'Neill P, Stewart RD. Induction and repair of clustered DNA lesions: what do we know so far? Radiat Res. 2013;180(1):100-9.
[63] Sage E, Harrison L. Clustered DNA lesion repair in eukaryotes: relevance to mutagenesis and cell survival. Mutat Res. 2011;711(1-2):123-33.
[64] Eccles LJ, O'Neill P, Lomax ME. Delayed repair of radiation induced clustered DNA damage: friend or foe? Mutat Res. 2011;711(1-2):134-41.
[65] Budworth H, Dianov GL. Mode of inhibition of short-patch base excision repair by thymine glycol within clustered DNA lesions. J Biol Chem. 2003;278(11):9378-81.
[66] Budworth H, Dianova II, Podust VN, Dianov GL. Repair of clustered DNA lesions. Sequence-specific inhibition of long-patch base excision repair be 8-oxoguanine. J Biol Chem. 2002;277(24):21300-5.
[67] Malyarchuk S, Castore R, Harrison L. DNA repair of clustered lesions in mammalian cells: involvement of non-homologous end-joining. Nucleic Acids Res. 2008;36(15):4872-82.
[68] Shikazono N, Noguchi M, Fujii K, Urushibara A, Yokoya A. The yield, processing, and biological consequences of clustered DNA damage induced by ionizing radiation. J Radiat Res. 2009;50(1):27-36.
[69] Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001;27(3):247-54.
[70] Clayton DA, Doda JN, Friedberg EC. The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A. 1974;71(7):2777-81.
[71] Pascucci B, Versteegh A, van Hoffen A, van Zeeland AA, Mullenders LH, Dogliotti E. DNA repair of UV photoproducts and mutagenesis in human mitochondrial DNA. J Mol Biol. 1997;273(2):417-27.
[72] Croteau DL, Stierum RH, Bohr VA. Mitochondrial DNA repair pathways. Mutat Res. 1999;434(3):137-48.
[73] Gredilla R, Bohr VA, Stevnsner T. Mitochondrial DNA repair and association with aging--an update. Exp Gerontol. 2010;45(7-8):478-88.
[74] LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K, Bohr VA. Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis. 1992;13(11):1967-73.
[75] Chattopadhyay R, Wiederhold L, Szczesny B, Boldogh I, Hazra TK, Izumi T, Mitra S. Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells. Nucleic Acids Res. 2006;34(7):2067-76.
[76] Nakabeppu Y. Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Prog Nucleic Acid Res Mol Biol. 2001;68:75-94.
[77] Gredilla R. DNA damage and base excision repair in mitochondria and their role in aging. J Aging Res. 2010;2011:257093.
[78] Szczesny B, Tann AW, Longley MJ, Copeland WC, Mitra S. Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem. 2008;283(39):26349-56.
[79] Alexeyev M, Shokolenko I, Wilson G, LeDoux S. The maintenance of mitochondrial DNA integrity--critical analysis and update. Cold Spring Harb Perspect Biol. 2013;5(5):a012641.
[80] de Souza-Pinto NC, Wilson DM 3rd, Stevnsner TV, Bohr VA. Mitochondrial DNA, base excision repair and neurodegeneration. DNA Repair (Amst). 2008;7(7):1098-109.
[81] Mitra S, Izumi T, Boldogh I, Bhakat KK, Chattopadhyay R, Szczesny B. Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein. DNA Repair (Amst). 2007;6(4):461-9.
[82] Copeland WC, Longley MJ. DNA polymerase gamma in mitochondrial DNA replication and repair. ScientificWorldJournal. 2003;3:34-44.
[83] Bailey CM, Anderson KS. A mechanistic view of human mitochondrial DNA polymerase gamma: providing insight into drug toxicity and mitochondrial disease. Biochim Biophys Acta. 2010;1804(5):1213-22.
[84] Lakshmipathy U, Campbell C. The human DNA ligase III gene encodes nuclear and mitochondrial proteins. Mol Cell Biol. 1999;19(5):3869-76.
[85] Lakshmipathy U, Campbell C. Mitochondrial DNA ligase III function is independent of Xrcc1. Nucleic Acids Res. 2000;28(20):3880-6.
[86] Wilson DM 3rd, Barsky D. The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA. Mutat Res. 2001;485(4):283-307.
[87] Demple B, Harrison L. Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem. 1994;63:915-48.
[88] Khodyreva S, Lavrik O. New players in recognition of intact and cleaved AP sites: implication in DNA repair in mammalian cells. In: "Selected topics in DNA Repair", InTech. 2011:305–30.
[89] Drohat AC, Maiti A. Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org Biomol Chem. 2014;12(42):8367-78.
[90] Akbari M, Morevati M, Croteau D, Bohr VA. The role of DNA base excision repair in brain homeostasis and disease. DNA Repair (Amst). 2015;32:172-9.
[91] Duxin JP, Dao B, Martinsson P, Rajala N, Guittat L, Campbell JL, Spelbrink JN, Stewart SA. Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol Cell Biol. 2009;29(15):4274-82.
[92] Zheng L, Zhou M, Guo Z, Lu H, Qian L, Dai H, Qiu J, Yakubovskaya E, Bogenhagen DF, Demple B, Shen B. Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol Cell. 2008;32(3):325-36.
[93] Kalifa L, Beutner G, Phadnis N, Sheu SS, Sia EA. Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity. DNA Repair (Amst). 2009;8(10):1242-9.
[94] Tann AW, Boldogh I, Meiss G, Qian W, Van Houten B, Mitra S, Szczesny B. Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5'-EXO/endonuclease) in their repair. J Biol Chem. 2011;286(37):31975-83.
[95] Hudson JJ, Chiang SC, Wells OS, Rookyard C, El-Khamisy SF. SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nat Commun. 2012;3:733.
[96] Rass U, Ahel I, West SC. Actions of aprataxin in multiple DNA repair pathways. J Biol Chem. 2007;282(13):9469-74.
[97] Pachkowski BF, Tano K, Afonin V, Elder RH, Takeda S, Watanabe M, Swenberg JA, Nakamura J. Cells deficient in PARP-1 show an accelerated accumulation of DNA single strand breaks, but not AP sites, over the PARP-1-proficient cells exposed to MMS. Mutat Res. 2009;671(1-2):93-9.
[98] Ström CE, Johansson F, Uhlén M, Szigyarto CA, Erixon K, Helleday T. Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res. 2011;39(8):3166-75.
[99] Harris JL, Jakob B, Taucher-Scholz G, Dianov GL, Becherel OJ, Lavin MF. Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage. Hum Mol Genet. 2009;18(21):4102-17.
[100] Rossi MN, Carbone M, Mostocotto C, Mancone C, Tripodi M, Maione R, Amati P. Mitochondrial localization of PARP-1 requires interaction with mitofilin and is involved in the maintenance of mitochondrial DNA integrity. J Biol Chem. 2009;284(46):31616-24.
[101] Scovassi AI. Mitochondrial poly(ADP-ribosylation): from old data to new perspectives. FASEB J. 2004;18(13):1487-8.
[102] Lapucci A, Pittelli M, Rapizzi E, Felici R, Moroni F, Chiarugi A. Poly(ADP-ribose) polymerase-1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription. Mol Pharmacol. 2011;79(6):932-40.
[103] Bürkle A, Virág L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med. 2013;34(6):1046-65.
[104] Szczesny B, Brunyanszki A, Olah G, Mitra S, Szabo C. Opposing roles of mitochondrial and nuclear PARP1 in the regulation of mitochondrial and nuclear DNA integrity: implications for the regulation of mitochondrial function. Nucleic Acids Res. 2014;42(21):13161-73.
[105] Coffey G, Lakshmipathy U, Campbell C. Mammalian mitochondrial extracts possess DNA end-binding activity. Nucleic Acids Res. 1999;27(16):3348-54.
[106] Tadi SK, Sebastian R, Dahal S, Babu RK, Choudhary B, Raghavan SC. Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions. Mol Biol Cell. 2016;27(2):223-35.
[107] Sage JM, Gildemeister OS, Knight KL. Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J Biol Chem. 2010;285(25):18984-90.
[108] Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC. Homology and enzymatic requirements of microhomology-dependent alternative end joining. Cell Death Dis. 2015;6:e1697.
[109] Clayton DA, Doda JN, Friedberg EC. The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A. 1974;71(7):2777-81.
[110] Olivero OA, Chang PK, Lopez-Larraza DM, Semino-Mora MC, Poirier MC. Preferential formation and decreased removal of cisplatin-DNA adducts in Chinese hamster ovary cell mitochondrial DNA as compared to nuclear DNA. Mutat Res. 1997;391(1-2):79-86.
[111] Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RL, Mackie H, Spoonde AY, Ackerman EJ, Coleman K, Tarone RE, Robbins JH. The oxidative DNA lesion 8,5'-(S)-cyclo-2'-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells. J Biol Chem. 2000;275(29):22355-62.
[112] Marietta C, Gulam H, Brooks PJ. A single 8,5'-cyclo-2'-deoxyadenosine lesion in a TATA box prevents binding of the TATA binding protein and strongly reduces transcription in vivo. DNA Repair (Amst). 2002;1(11):967-75.
[113] Aamann MD, Sorensen MM, Hvitby C, Berquist BR, Muftuoglu M, Tian J, de Souza-Pinto NC, Scheibye-Knudsen M, Wilson DM 3rd, Stevnsner T, Bohr VA. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane. FASEB J. 2010;24(7):2334-46.
[114] Kamenisch Y, Fousteri M, Knoch J, von Thaler AK, Fehrenbacher B, Kato H, Becker T, Dollé ME, Kuiper R, Majora M, Schaller M, van der Horst GT, van Steeg H, Röcken M, Rapaport D, Krutmann J, Mullenders LH, Berneburg M. Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. J Exp Med. 2010;207(2):379-90.
[115] Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC, Minor RK, Wilson DM 3rd, Cooper M, Spencer R, de Cabo R, Croteau DL, Bohr VA. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J Exp Med. 2012;209(4):855-69.
[116] Rooney JP, Ryde IT, Sanders LH, Howlett EH, Colton MD, Germ KE, Mayer GD, Greenamyre JT, Meyer JN. PCR based determination of mitochondrial DNA copy number in multiple species. Methods Mol Biol. 2015;1241:23-38.
[117] Alexeyev MF, Venediktova N, Pastukh V, Shokolenko I, Bonilla G, Wilson GL. Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther. 2008;15(7):516-23.
[118] Shokolenko IN, Wilson GL, Alexeyev MF. Persistent damage induces mitochondrial DNA degradation. DNA Repair (Amst). 2013;12(7):488-99.
[119] Bacman SR, Williams SL, Moraes CT. Intra- and inter-molecular recombination of mitochondrial DNA after in vivo induction of multiple double-strand breaks. Nucleic Acids Res. 2009;37(13):4218-26.
[120] Mita S, Monnat RJ Jr, Loeb LA. Resistance of HeLa cell mitochondrial DNA to mutagenesis by chemical carcinogens. Cancer Res. 1988;48(16):4578-83.
[121] Ikeda S, Ozaki K. Action of mitochondrial endonuclease G on DNA damaged by L-ascorbic acid, peplomycin, and cis-diamminedichloroplatinum (II). Biochem Biophys Res Commun. 1997;235(2):291-4.
[122] Greinert R, Volkmer B, Henning S, Breitbart EW, Greulich KO, Cardoso MC, Rapp A. UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages. Nucleic Acids Res. 2012;40(20):10263-73.
[123] Gulston M, de Lara C, Jenner T, Davis E, O'Neill P. Processing of clustered DNA damage generates additional double-strand breaks in mammalian cells post-irradiation. Nucleic Acids Res. 2004;32(4):1602-9.
[124] Georgakilas AG, Bennett PV, Wilson DM 3rd, Sutherland BM. Processing of bistranded abasic DNA clusters in gamma-irradiated human hematopoietic cells. Nucleic Acids Res. 2004;32(18):5609-20.
[125] Malyarchuk S, Harrison L. DNA repair of clustered uracils in HeLa cells. J Mol Biol. 2005;345(4):731-43.
[126] Malyarchuk S, Castore R, Harrison L. Apex1 can cleave complex clustered DNA lesions in cells. DNA Repair (Amst). 2009;8(12):1343-54.