Mitochondrial DNA maintenance: an appraisal

Molecular and Cellular Biochemistry

Volumn 409, Issue 1-2, 2015, Pages 283-305

  Akhmedov, Alexander T ^a   Marín García, José ^a  

^a The Molecular Cardiology and Neuromuscular Institute   (United States)

Author keywords

CVD; mtDNA; mtDNA repair; mtDNA replication; Nucleoid

Indexed keywords

DNA DIRECTED DNA POLYMERASE GAMMA; DNA HELICASE; DNA2 PROTEIN; MITOCHONDRIAL DNA; MITOCHONDRIAL TRANSCRIPTION FACTOR A; TWINKLE PROTEIN; UNCLASSIFIED DRUG;

AGING; DNA DAMAGE; DNA REPAIR; EXCISION REPAIR; GENE MUTATION; HEART INJURY; HUMAN; MITOCHONDRIAL DNA DEPLETION; MITOCHONDRIAL DNA DISORDER; MITOCHONDRIAL DNA REPLICATION; MITOCHONDRIAL GENOME; NONHUMAN; PROTEIN FUNCTION; REPLISOME; REVIEW; DNA REPLICATION; ENERGY METABOLISM; GENETICS; METABOLISM; MITOCHONDRION;

AGING; DNA DAMAGE; DNA HELICASES; DNA REPAIR; DNA REPLICATION; DNA, MITOCHONDRIAL; ENERGY METABOLISM; HUMANS; MITOCHONDRIA;

EID: 84942990347     PISSN: 03008177     EISSN: 15734919     Source Type: Journal    
DOI: 10.1007/s11010-015-2532-x     Document Type: Review

References (311)

1. Cadenas S, Aragones J, Landazuri MO (2010) Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease. Cardiovasc Res 88:219–228
2. Rosca MG, Hoppel CL (2010) Mitochondria in heart failure. Cardiovasc Res 88:40–50
3. Wong LJ (2010) Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 16:154–162
4. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159
5. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698
6. Clayton DA (1991) Replication and transcription of vertebrate mitochondrial DNA. Annu Rev Cell Biol 7:453–478
7. Chen XJ, Butow RA (2005) The organization and inheritance of the mitochondrial genome. Nat Rev Genet 6:815–825
8. Holt IJ (2009) Mitochondrial DNA replication and repair: all a flap. Trends Biochem Sci 34:358–365
9. McKinney EA, Oliveira MT (2013) Replicating animal mitochondrial DNA. Genet Mol Biol 36:308–315
10. Kucej M, Butow RA (2007) Evolutionary tinkering with mitochondrial nucleoids. Trends Cell Biol 17:586–592
11. Spelbrink JN (2010) Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life 62:19–32
12. Bogenhagen DF (2012) Mitochondrial DNA nucleoid structure. Biochim Biophys Acta 1819:914–920
13. Hensen F, Cansiz S, Gerhold JM, Spelbrink JN (2014) To be or not to be a nucleoid protein: a comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins. Biochimie 100:219–226
14. Wanrooij S, Falkenberg M (2010) The human mitochondrial replication fork in health and disease. Biochim Biophys Acta 1797:1378–1388
15. Gaston D, Tsaousis AD, Roger AJ (2009) Predicting proteomes of mitochondria and related organelles from genomic and expressed sequence tag data. Methods Enzymol 457:21–47
16. Calvo SE, Mootha VK (2010) The mitochondrial proteome and human disease. Annu Rev Genomics Hum Genet 11:25–44
17. Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138:628–644
18. Schmidt O, Pfanner N, Meisinger C (2010) Mitochondrial protein import: from proteomics to functional mechanisms. Nat Rev Mol Cell Biol 11:655–667
19. Ryan MT, Hoogenraad NJ (2007) Mitochondrial-nuclear communications. Annu Rev Biochem 76:701–722
20. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278
21. Kasiviswanathan R, Collins TR, Copeland WC (2012) The interface of transcription and DNA replication in the mitochondria. Biochim Biophys Acta 1819:970–978
22. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M (2004) Reconstitution of a minimal mtDNA replisome in vitro. EMBO J 23:2423–2429
23. Copeland WC, Longley MJ (2014) Mitochondrial genome maintenance in health and disease. DNA Repair (Amst) 19:190–198
24. Shutt TE, Gray MW (2006) Bacteriophage origins of mitochondrial replication and transcription proteins. Trends Genet 22:90–95
25. Kaguni LS (2004) DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 73:293–320
26. Graziewicz MA, Longley MJ, Copeland WC (2006) DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev 106:383–405
27. Carrodeguas JA, Theis K, Bogenhagen DF, Kisker C (2001) Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer. Mol Cell 7:43–54
28. Yakubovskaya E, Chen Z, Carrodeguas JA, Kisker C, Bogenhagen DF (2006) Functional human mitochondrial DNA polymerase gamma forms a heterotrimer. J Biol Chem 281:374–382
29. Lim SE, Longley MJ, Copeland WC (1999) The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethylmaleimide resistance. J Biol Chem 274:38197–38203
30. Yakubovskaya E, Lukin M, Chen Z, Berriman J, Wall JS et al (2007) The EM structure of human DNA polymerase gamma reveals a localized contact between the catalytic and accessory subunits. EMBO J 26:4283–4291
31. Lee YS, Kennedy WD, Yin YW (2009) Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations. Cell 139:312–324
32. Lee YS, Lee S, Demeler B, Molineux IJ, Johnson KA et al (2010) Each monomer of the dimeric accessory protein for human mitochondrial DNA polymerase has a distinct role in conferring processivity. J Biol Chem 285:1490–1499
33. Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM et al (2003) Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell 14:1583–1596
34. Bogenhagen DF, Wang Y, Shen EL, Kobayashi R (2003) Protein components of mitochondrial DNA nucleoids in higher eukaryotes. Mol Cell Proteomics 2:1205–1216
35. Wang Y, Bogenhagen DF (2006) Human mitochondrial DNA nucleoids are linked to protein folding machinery and metabolic enzymes at the mitochondrial inner membrane. J Biol Chem 281:25791–25802
36. Bogenhagen DF, Rousseau D, Burke S (2008) The layered structure of human mitochondrial DNA nucleoids. J Biol Chem 283:3665–3675
37. Curth U, Urbanke C, Greipel J, Gerberding H, Tiranti V et al (1994) Single-stranded-DNA-binding proteins from human mitochondria and Escherichia coli have analogous physicochemical properties. Eur J Biochem 221:435–443
38. Yang C, Curth U, Urbanke C, Kang C (1997) Crystal structure of human mitochondrial single-stranded DNA binding protein at 2.4 A resolution. Nat Struct Biol 4:153–157
39. Takamatsu C, Umeda S, Ohsato T, Ohno T, Abe Y et al (2002) Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. EMBO Rep 3:451–456
40. Van Dyck E, Foury F, Stillman B, Brill SJ (1992) A single-stranded DNA binding protein required for mitochondrial DNA replication in S. cerevisiae is homologous to E. coli SSB. EMBO J 11:3421–3430
41. Maier D, Farr CL, Poeck B, Alahari A, Vogel M et al (2001) Mitochondrial single-stranded DNA-binding protein is required for mitochondrial DNA replication and development in Drosophila melanogaster. Mol Biol Cell 12:821–830
42. Farr CL, Matsushima Y, Lagina AT 3rd, Luo N, Kaguni LS (2004) Physiological and biochemical defects in functional interactions of mitochondrial DNA polymerase and DNA-binding mutants of single-stranded DNA-binding protein. J Biol Chem 279:17047–17053
43. Fisher RP, Clayton DA (1988) Purification and characterization of human mitochondrial transcription factor 1. Mol Cell Biol 8:3496–3509
44. Parisi MA, Clayton DA (1991) Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252:965–969
45. Dairaghi DJ, Shadel GS, Clayton DA (1995) Addition of a 29 residue carboxyl-terminal tail converts a simple HMG box-containing protein into a transcriptional activator. J Mol Biol 249:11–28
46. Kanki T, Ohgaki K, Gaspari M, Gustafsson CM, Fukuoh A et al (2004) Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol 24:9823–9834
47. Fisher RP, Lisowsky T, Parisi MA, Clayton DA (1992) DNA wrapping and bending by a mitochondrial high mobility group-like transcriptional activator protein. J Biol Chem 267:3358–3367
48. Farge G, Laurens N, Broekmans OD, van den Wildenberg SM, Dekker LC et al (2012) Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A. Nat Commun 3:1013
49. Ngo HB, Kaiser JT, Chan DC (2011) The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol 18:1290–1296
50. Rubio-Cosials A, Sidow JF, Jimenez-Menendez N, Fernandez-Millan P, Montoya J et al (2011) Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nat Struct Mol Biol 18:1281–1289
51. Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG et al (2011) Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc Natl Acad Sci USA 108:13534–13539
52. Alam TI, Kanki T, Muta T, Ukaji K, Abe Y et al (2003) Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res 31:1640–1645
53. Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M et al (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944
54. Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P et al (1998) Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 18:231–236
55. Freyer C, Park CB, Ekstrand MI, Shi Y, Khvorostova J et al (2010) Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription. Nucleic Acids Res 38:6577–6588
56. Patel SS, Donmez I (2006) Mechanisms of helicases. J Biol Chem 281:18265–18268
57. Singleton MR, Dillingham MS, Wigley DB (2007) Structure and mechanism of helicases and nucleic acid translocases. Annu Rev Biochem 76:23–50
58. Dillingham MS (2011) Superfamily I helicases as modular components of DNA-processing machines. Biochem Soc Trans 39:413–423
59. Hubscher U (2009) DNA replication fork proteins. Methods Mol Biol 521:19–33
60. Bernstein KA, Gangloff S, Rothstein R (2010) The RecQ DNA helicases in DNA repair. Annu Rev Genet 44:393–417
61. Singh DK, Ghosh AK, Croteau DL, Bohr VA (2012) RecQ helicases in DNA double strand break repair and telomere maintenance. Mutat Res 736:15–24
62. Wu Y (2012) Unwinding and rewinding: double faces of helicase? J Nucleic Acids 2012:140601
63. Picha KM, Ahnert P, Patel SS (2000) DNA binding in the central channel of bacteriophage T7 helicase-primase is a multistep process. Nucleotide hydrolysis is not required. Biochemistry 39:6401–6409
64. Fanning E, Knippers R (1992) Structure and function of simian virus 40 large tumor antigen. Annu Rev Biochem 61:55–85
65. Ahnert P, Picha KM, Patel SS (2000) A ring-opening mechanism for DNA binding in the central channel of the T7 helicase-primase protein. EMBO J 19:3418–3427
66. Egelman EH, Yu X, Wild R, Hingorani MM, Patel SS (1995) Bacteriophage T7 helicase/primase proteins form rings around single-stranded DNA that suggest a general structure for hexameric helicases. Proc Natl Acad Sci USA 92:3869–3873
67. Morris PD, Raney KD (1999) DNA helicases displace streptavidin from biotin-labeled oligonucleotides. Biochemistry 38:5164–5171
68. Patel SS, Picha KM (2000) Structure and function of hexameric helicases. Annu Rev Biochem 69:651–697
69. Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP et al (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28:223–231
70. Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH et al (2008) Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia. J Mol Biol 377:691–705
71. Ziebarth TD, Farr CL, Kaguni LS (2007) Modular architecture of the hexameric human mitochondrial DNA helicase. J Mol Biol 367:1382–1391
72. Farge G, Holmlund T, Khvorostova J, Rofougaran R, Hofer A et al (2008) The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities. Nucleic Acids Res 36:393–403
73. Shutt TE, Gray MW (2006) Twinkle, the mitochondrial replicative DNA helicase, is widespread in the eukaryotic radiation and may also be the mitochondrial DNA primase in most eukaryotes. J Mol Evol 62:588–599
74. Diray-Arce J, Liu B, Cupp JD, Hunt T, Nielsen BL (2013) The Arabidopsis At1g30680 gene encodes a homologue to the phage T7 gp4 protein that has both DNA primase and DNA helicase activities. BMC Plant Biol 13:36
75. Ziebarth TD, Gonzalez-Soltero R, Makowska-Grzyska MM, Nunez-Ramirez R, Carazo JM et al (2010) Dynamic effects of cofactors and DNA on the oligomeric state of human mitochondrial DNA helicase. J Biol Chem 285:14639–14647
76. Sen D, Nandakumar D, Tang GQ, Patel SS (2012) Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase. J Biol Chem 287:14545–14556
77. Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A et al (2009) Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet 18:328–340
78. Jemt E, Farge G, Backstrom S, Holmlund T, Gustafsson CM et al (2011) The mitochondrial DNA helicase TWINKLE can assemble on a closed circular template and support initiation of DNA synthesis. Nucleic Acids Res 39:9238–9249
79. Korhonen JA, Gaspari M, Falkenberg M (2003) TWINKLE Has 5′ → 3′ DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. J Biol Chem 278:48627–48632
80. Wanrooij S, Goffart S, Pohjoismaki JL, Yasukawa T, Spelbrink JN (2007) Expression of catalytic mutants of the mtDNA helicase Twinkle and polymerase POLG causes distinct replication stalling phenotypes. Nucleic Acids Res 35:3238–3251
81. Matsushima Y, Farr CL, Fan L, Kaguni LS (2008) Physiological and biochemical defects in carboxyl-terminal mutants of mitochondrial DNA helicase. J Biol Chem 283:23964–23971
82. Hingorani MM, Patel SS (1993) Interactions of bacteriophage T7 DNA primase/helicase protein with single-stranded and double-stranded DNAs. Biochemistry 32:12478–12487
83. Milenkovic D, Matic S, Kuhl I, Ruzzenente B, Freyer C et al (2013) TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication. Hum Mol Genet 22:1983–1993
84. Garcia PL, Liu Y, Jiricny J, West SC, Janscak P (2004) Human RECQ5beta, a protein with DNA helicase and strand-annealing activities in a single polypeptide. EMBO J 23:2882–2891
85. Cheok CF, Wu L, Garcia PL, Janscak P, Hickson ID (2005) The Bloom’s syndrome helicase promotes the annealing of complementary single-stranded DNA. Nucleic Acids Res 33:3932–3941
86. Machwe A, Xiao L, Groden J, Matson SW, Orren DK (2005) RecQ family members combine strand pairing and unwinding activities to catalyze strand exchange. J Biol Chem 280:23397–23407
87. Xu X, Liu Y (2009) Dual DNA unwinding activities of the Rothmund-Thomson syndrome protein, RECQ4. EMBO J 28:568–577
88. Pohjoismaki JL, Goffart S, Tyynismaa H, Willcox S, Ide T et al (2009) Human heart mitochondrial DNA is organized in complex catenated networks containing abundant four-way junctions and replication forks. J Biol Chem 284:21446–21457
89. Budd ME, Campbell JL (1995) A yeast gene required for DNA replication encodes a protein with homology to DNA helicases. Proc Natl Acad Sci USA 92:7642–7646
90. Eki T, Okumura K, Shiratori A, Abe M, Nogami M et al (1996) Assignment of the closest human homologue (DNA2L:KIAA0083) of the yeast Dna2 helicase gene to chromosome band 10q21.3-q22.1. Genomics 37:408–410
91. Liu Q, Choe W, Campbell JL (2000) Identification of the Xenopus laevis homolog of Saccharomyces cerevisiae DNA2 and its role in DNA replication. J Biol Chem 275:1615–1624
92. Lee KH, Lee MH, Lee TH, Han JW, Park YJ et al (2003) Dna2 requirement for normal reproduction of Caenorhabditis elegans is temperature-dependent. Mol Cells 15:81–86
93. Kim JH, Kim HD, Ryu GH, Kim DH, Hurwitz J et al (2006) Isolation of human Dna2 endonuclease and characterization of its enzymatic properties. Nucleic Acids Res 34:1854–1864
94. Masuda-Sasa T, Imamura O, Campbell JL (2006) Biochemical analysis of human Dna2. Nucleic Acids Res 34:1865–1875
95. Bae SH, Seo YS (2000) Characterization of the enzymatic properties of the yeast dna2 Helicase/endonuclease suggests a new model for Okazaki fragment processing. J Biol Chem 275:38022–38031
96. Bae SH, Kim DW, Kim J, Kim JH, Kim DH et al (2002) Coupling of DNA helicase and endonuclease activities of yeast Dna2 facilitates Okazaki fragment processing. J Biol Chem 277:26632–26641
97. Bae SH, Bae KH, Kim JA, Seo YS (2001) RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature 412:456–461
98. Okazaki R, Okazaki T, Sakabe K, Sugimoto K, Sugino A (1968) Mechanism of DNA chain growth. I. Possible discontinuity and unusual secondary structure of newly synthesized chains. Proc Natl Acad Sci USA 59:598–605
99. Kang YH, Lee CH, Seo YS (2010) Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes. Crit Rev Biochem Mol Biol 45:71–96
100. Budd ME, Campbell JL (2000) The pattern of sensitivity of yeast dna2 mutants to DNA damaging agents suggests a role in DSB and postreplication repair pathways. Mutat Res 459:173–186
101. Zheng L, Zhou M, Guo Z, Lu H, Qian L et al (2008) Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol Cell 32:325–336
102. Masuda-Sasa T, Polaczek P, Campbell JL (2006) Single strand annealing and ATP-independent strand exchange activities of yeast and human DNA2: possible role in Okazaki fragment maturation. J Biol Chem 281:38555–38564
103. Duxin JP, Dao B, Martinsson P, Rajala N, Guittat L et al (2009) Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol Cell Biol 29:4274–4282
104. Duxin JP, Moore HR, Sidorova J, Karanja K, Honaker Y et al (2012) Okazaki fragment processing-independent role for human Dna2 enzyme during DNA replication. J Biol Chem 287:21980–21991
105. Peng G, Dai H, Zhang W, Hsieh HJ, Pan MR et al (2012) Human nuclease/helicase DNA2 alleviates replication stress by promoting DNA end resection. Cancer Res 72:2802–2813
106. Boule JB, Zakian VA (2006) Roles of Pif1-like helicases in the maintenance of genomic stability. Nucleic Acids Res 34:4147–4153
107. Bochman ML, Sabouri N, Zakian VA (2010) Unwinding the functions of the Pif1 family helicases. DNA Repair (Amst) 9:237–249
108. Szczesny RJ, Wojcik MA, Borowski LS, Szewczyk MJ, Skrok MM et al (2013) Yeast and human mitochondrial helicases. Biochim Biophys Acta 1829:842–853
109. Foury F, Kolodynski J (1983) pif mutation blocks recombination between mitochondrial rho + and rho- genomes having tandemly arrayed repeat units in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 80:5345–5349
110. Lahaye A, Stahl H, Thines-Sempoux D, Foury F (1991) PIF1: a DNA helicase in yeast mitochondria. EMBO J 10:997–1007
111. Keil RL, McWilliams AD (1993) A gene with specific and global effects on recombination of sequences from tandemly repeated genes in Saccharomyces cerevisiae. Genetics 135:711–718
112. Ivessa AS, Zhou JQ, Zakian VA (2000) The Saccharomyces Pif1p DNA helicase and the highly related Rrm3p have opposite effects on replication fork progression in ribosomal DNA. Cell 100:479–489
113. Bochman ML, Judge CP, Zakian VA (2011) The Pif1 family in prokaryotes: what are our helicases doing in your bacteria? Mol Biol Cell 22:1955–1959
114. Mateyak MK, Zakian VA (2006) Human PIF helicase is cell cycle regulated and associates with telomerase. Cell Cycle 5:2796–2804
115. Futami K, Shimamoto A, Furuichi Y (2007) Mitochondrial and nuclear localization of human Pif1 helicase. Biol Pharm Bull 30:1685–1692
116. Huang Y, Zhang DH, Zhou JQ (2006) Characterization of ATPase activity of recombinant human Pif1. Acta Biochim Biophys Sin (Shanghai) 38:335–341
117. Zhang DH, Zhou B, Huang Y, Xu LX, Zhou JQ (2006) The human Pif1 helicase, a potential Escherichia coli RecD homologue, inhibits telomerase activity. Nucleic Acids Res 34:1393–1404
118. Gu Y, Masuda Y, Kamiya K (2008) Biochemical analysis of human PIF1 helicase and functions of its N-terminal domain. Nucleic Acids Res 36:6295–6308
119. George T, Wen Q, Griffiths R, Ganesh A, Meuth M et al (2009) Human Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks. Nucleic Acids Res 37:6491–6502
120. Gu Y, Wang J, Li S, Kamiya K, Chen X et al (2013) Determination of the biochemical properties of full-length human PIF1 ATPase. Prion 7:341–347
121. Snow BE, Mateyak M, Paderova J, Wakeham A, Iorio C et al (2007) Murine Pif1 interacts with telomerase and is dispensable for telomere function in vivo. Mol Cell Biol 27:1017–1026
122. Halliwell B, Gutteridge JM (1984) Free radicals, lipid peroxidation, and cell damage. Lancet 2:1095
123. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922
124. Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472
125. Cadet J, Douki T, Ravanat JL (2010) Oxidatively generated base damage to cellular DNA. Free Radic Biol Med 49:9–21
126. Roede JR, Jones DP (2010) Reactive species and mitochondrial dysfunction: mechanistic significance of 4-hydroxynonenal. Environ Mol Mutagen 51:380–390
127. Yin H, Xu L, Porter NA (2011) Free radical lipid peroxidation: mechanisms and analysis. Chem Rev 111:5944–5972
128. 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 94:514–519
129. Stumpf JD, Copeland WC (2011) Mitochondrial DNA replication and disease: insights from DNA polymerase gamma mutations. Cell Mol Life Sci 68:219–233
130. Tang S, Wang J, Lee NC, Milone M, Halberg MC et al (2011) Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 48:669–681
131. Stumpf JD, Saneto RP, Copeland WC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5:a011395
132. Longley MJ, Ropp PA, Lim SE, Copeland WC (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
133. Longley MJ, Nguyen D, Kunkel TA, Copeland WC (2001) The fidelity of human DNA polymerase gamma with and without exonucleolytic proofreading and the p55 accessory subunit. J Biol Chem 276:38555–38562
134. Cortopassi GA, Shibata D, Soong NW, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 89:7370–7374
135. Larsson NG, Clayton DA (1995) Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet 29:151–178
136. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286:774–779
137. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS et al (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39:540–543
138. Williams SL, Huang J, Edwards YJ, Ulloa RH, Dillon LM et al (2010) The mtDNA mutation spectrum of the progeroid Polg mutator mouse includes abundant control region multimers. Cell Metab 12:675–682
139. Niranjan BG, Bhat NK, Avadhani NG (1982) Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science 215:73–75
140. Vaisman A, Lim SE, Patrick SM, Copeland WC, Hinkle DC et al (1999) Effect of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts. Biochemistry 38:11026–11039
141. Graziewicz MA, Sayer JM, Jerina DM, Copeland WC (2004) Nucleotide incorporation by human DNA polymerase gamma opposite benzo[a]pyrene and benzo[c]phenanthrene diol epoxide adducts of deoxyguanosine and deoxyadenosine. Nucleic Acids Res 32:397–405
142. Kasiviswanathan R, Gustafson MA, Copeland WC, Meyer JN (2012) Human mitochondrial DNA polymerase gamma exhibits potential for bypass and mutagenesis at UV-induced cyclobutane thymine dimers. J Biol Chem 287:9222–9229
143. Cline SD (2012) Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim Biophys Acta 1819:979–991
144. Singer TP, Ramsay RR (1990) Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett 274:1–8
145. Bandy B, Davison AJ (1990) Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 8:523–539
146. De Bont R, van Larebeke N (2004) Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19:169–185
147. Jaruga P, Dizdaroglu M (2008) 8,5′-Cyclopurine-2′-deoxynucleosides in DNA: mechanisms of formation, measurement, repair and biological effects. DNA Repair (Amst) 7:1413–1425
148. Swenberg JA, Fryar-Tita E, Jeong YC, Boysen G, Starr T et al (2008) Biomarkers in toxicology and risk assessment: informing critical dose-response relationships. Chem Res Toxicol 21:253–265
149. Taghizadeh K, McFaline JL, Pang B, Sullivan M, Dong M et al (2008) Quantification of DNA damage products resulting from deamination, oxidation and reaction with products of lipid peroxidation by liquid chromatography isotope dilution tandem mass spectrometry. Nat Protoc 3:1287–1298
150. Hunter SE, Jung D, Di Giulio RT, Meyer JN (2010) The QPCR assay for analysis of mitochondrial DNA damage, repair, and relative copy number. Methods 51:444–451
151. Garcia CC, Freitas FP, Di Mascio P, Medeiros MH (2010) Ultrasensitive simultaneous quantification of 1, N2-etheno-2′-deoxyguanosine and 1, N2-propano-2′-deoxyguanosine in DNA by an online liquid chromatography-electrospray tandem mass spectrometry assay. Chem Res Toxicol 23:1245–1255
152. Nair J, Nair UJ, Sun X, Wang Y, Arab K et al (2011) Quantifying etheno-DNA adducts in human tissues, white blood cells, and urine by ultrasensitive (32)P-postlabeling and immunohistochemistry. Methods Mol Biol 682:189–205
153. Cadet J, Douki T, Ravanat JL (2011) Measurement of oxidatively generated base damage in cellular DNA. Mutat Res 711:3–12
154. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214
155. Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM et al (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 34:609–616
156. Nakamura J, Swenberg JA (1999) Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res 59:2522–2526
157. Atamna H, Cheung I, Ames BN (2000) A method for detecting abasic sites in living cells: age-dependent changes in base excision repair. Proc Natl Acad Sci USA 97:686–691
158. Shokolenko I, Venediktova N, Bochkareva A, Wilson GL, Alexeyev MF (2009) Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res 37:2539–2548
159. Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9:619–631
160. McKinnon PJ, Caldecott KW (2007) DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 8:37–55
161. Kasparek TR, Humphrey TC (2011) DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol 22:886–897
162. Rothfuss O, Gasser T, Patenge N (2010) Analysis of differential DNA damage in the mitochondrial genome employing a semi-long run real-time PCR approach. Nucleic Acids Res 38:e24
163. Furda AM, Marrangoni AM, Lokshin A, Van Houten B (2012) Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction. DNA Repair (Amst) 11:684–692
164. Liu P, Demple B (2010) DNA repair in mammalian mitochondria: much more than we thought? Environ Mol Mutagen 51:417–426
165. Kazak L, Reyes A, Holt IJ (2012) Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat Rev Mol Cell Biol 13:659–671
166. Sykora P, Wilson DM 3rd, Bohr VA (2012) Repair of persistent strand breaks in the mitochondrial genome. Mech Ageing Dev 133:169–175
167. Alexeyev M, Shokolenko I, Wilson G, LeDoux S (2013) The maintenance of mitochondrial DNA integrity–critical analysis and update. Cold Spring Harb Perspect Biol 5:a012641
168. Clayton DA, Doda JN, Friedberg EC (1974) The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci USA 71:2777–2781
169. Clayton DA, Doda JN, Friedberg EC (1975) Absence of a pyrimidine dimer repair mechanism for mitochondrial DNA in mouse and human cells. Basic Life Sci 5B:589–591
170. Pascucci B, Versteegh A, van Hoffen A, van Zeeland AA, Mullenders LH et al (1997) DNA repair of UV photoproducts and mutagenesis in human mitochondrial DNA. J Mol Biol 273:417–427
171. Olivero OA, Chang PK, Lopez-Larraza DM, Semino-Mora MC, Poirier MC (1997) Preferential formation and decreased removal of cisplatin-DNA adducts in Chinese hamster ovary cell mitochondrial DNA as compared to nuclear DNA. Mutat Res 391:79–86
172. Lloyd DR, Hanawalt PC (2000) p53-dependent global genomic repair of benzo[a]pyrene-7,8-diol-9,10-epoxide adducts in human cells. Cancer Res 60:517–521
173. Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ et al (2000) 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 275:22355–22362
174. Larsen NB, Rasmussen M, Rasmussen LJ (2005) Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion 5:89–108
175. Stuart JA, Brown MF (2006) Mitochondrial DNA maintenance and bioenergetics. Biochim Biophys Acta 1757:79–89
176. Druzhyna NM, Wilson GL, LeDoux SP (2008) Mitochondrial DNA repair in aging and disease. Mech Ageing Dev 129:383–390
177. Chen XJ (2013) Mechanism of homologous recombination and implications for aging-related deletions in mitochondrial DNA. Microbiol Mol Biol Rev 77:476–496
178. LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K et al (1992) Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis 13:1967–1973
179. Driggers WJ, LeDoux SP, Wilson GL (1993) Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells. J Biol Chem 268:22042–22045
180. LeDoux SP, Driggers WJ, Hollensworth BS, Wilson GL (1999) Repair of alkylation and oxidative damage in mitochondrial DNA. Mutat Res 434:149–159
181. Szczesny B, Tann AW, Longley MJ, Copeland WC, Mitra S (2008) Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 283:26349–26356
182. Svilar D, Goellner EM, Almeida KH, Sobol RW (2011) Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage. Antioxid Redox Signal 14:2491–2507
183. Thorslund T, Sunesen M, Bohr VA, Stevnsner T (2002) Repair of 8-oxoG is slower in endogenous nuclear genes than in mitochondrial DNA and is without strand bias. DNA Repair (Amst) 1:261–273
184. Bohr VA (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32:804–812
185. Akbari M, Visnes T, Krokan HE, Otterlei M (2008) Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. DNA Repair (Amst) 7:605–616
186. Liu P, Qian L, Sung JS, de Souza-Pinto NC, Zheng L et al (2008) Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria. Mol Cell Biol 28:4975–4987
187. Almeida KH, Sobol RW (2007) A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair (Amst) 6:695–711
188. Gredilla R, Garm C, Stevnsner T (2012) Nuclear and mitochondrial DNA repair in selected eukaryotic aging model systems. Oxidative Med Cell Longev 2012:282438
189. Dizdaroglu M (2005) Base-excision repair of oxidative DNA damage by DNA glycosylases. Mutat Res 591:45–59
190. Huffman JL, Sundheim O, Tainer JA (2005) DNA base damage recognition and removal: new twists and grooves. Mutat Res 577:55–76
191. Dodson ML, Lloyd RS (2002) Mechanistic comparisons among base excision repair glycosylases. Free Radic Biol Med 32:678–682
192. Anderson CT, Friedberg EC (1980) The presence of nuclear and mitochondrial uracil-DNA glycosylase in extracts of human KB cells. Nucleic Acids Res 8:875–888
193. Ohtsubo T, Nishioka K, Imaiso Y, Iwai S, Shimokawa H et al (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 28:1355–1364
194. Caradonna S, Ladner R, Hansbury M, Kosciuk M, Lynch F et al (1996) Affinity purification and comparative analysis of two distinct human uracil-DNA glycosylases. Exp Cell Res 222:345–359
195. Nilsen H, Otterlei M, Haug T, Solum K, Nagelhus TA et al (1997) Nuclear and mitochondrial uracil-DNA glycosylases are generated by alternative splicing and transcription from different positions in the UNG gene. Nucleic Acids Res 25:750–755
196. de Souza-Pinto NC, Eide L, Hogue BA, Thybo T, Stevnsner T et al (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 61:5378–5381
197. 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 278:33701–33707
198. Hu J, de Souza-Pinto NC, Haraguchi K, Hogue BA, Jaruga P et al (2005) Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes. J Biol Chem 280:40544–40551
199. Mandal SM, Hegde ML, Chatterjee A, Hegde PM, Szczesny B et al (2012) Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3′-phosphatase in maintenance of mitochondrial genome. J Biol Chem 287:2819–2829
200. Nishioka K, Ohtsubo T, Oda H, Fujiwara T, Kang D et al (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 10:1637–1652
201. Takao M, Aburatani H, Kobayashi K, Yasui A (1998) Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Nucleic Acids Res 26:2917–2922
202. Stierum RH, Croteau DL, Bohr VA (1999) Purification and characterization of a mitochondrial thymine glycol endonuclease from rat liver. J Biol Chem 274:7128–7136
203. Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW et al (2002) Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci USA 99:3523–3528
204. Morland I, Rolseth V, Luna L, Rognes T, Bjoras M et al (2002) Human DNA glycosylases of the bacterial Fpg/MutM superfamily: an alternative pathway for the repair of 8-oxoguanine and other oxidation products in DNA. Nucleic Acids Res 30:4926–4936
205. Ide H, Kotera M (2004) Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull 27:480–485
206. Wilson DM 3rd, Barsky D (2001) The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA. Mutat Res 485:283–307
207. Demple B, Sung JS (2005) Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair (Amst) 4:1442–1449
208. Wilson TM, Rivkees SA, Deutsch WA, Kelley MR (1996) Differential expression of the apurinic/apyrimidinic endonuclease (APE/ref-1) multifunctional DNA base excision repair gene during fetal development and in adult rat brain and testis. Mutat Res 362:237–248
209. Fung H, Kow YW, Van Houten B, Taatjes DJ, Hatahet Z et al (1998) Asbestos increases mammalian AP-endonuclease gene expression, protein levels, and enzyme activity in mesothelial cells. Cancer Res 58:189–194
210. Chattopadhyay R, Wiederhold L, Szczesny B, Boldogh I, Hazra TK et al (2006) Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells. Nucleic Acids Res 34:2067–2076
211. 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 95:12244–12248
212. Tahbaz N, Subedi S, Weinfeld M (2012) Role of polynucleotide kinase/phosphatase in mitochondrial DNA repair. Nucleic Acids Res 40:3484–3495
213. Hegde ML, Hazra TK, Mitra S (2008) Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res 18:27–47
214. Tann AW, Boldogh I, Meiss G, Qian W, Van Houten B et al (2011) Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5′-EXO/endonuclease) in their repair. J Biol Chem 286:31975–31983
215. Cymerman IA, Chung I, Beckmann BM, Bujnicki JM, Meiss G (2008) EXOG, a novel paralog of Endonuclease G in higher eukaryotes. Nucleic Acids Res 36:1369–1379
216. Kornblum C, Nicholls TJ, Haack TB, Scholer S, Peeva V et al (2013) Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet 45:214–219
217. Szczesny RJ, Hejnowicz MS, Steczkiewicz K, Muszewska A, Borowski LS et al (2013) Identification of a novel human mitochondrial endo-/exonuclease Ddk1/c20orf72 necessary for maintenance of proper 7S DNA levels. Nucleic Acids Res 41:3144–3161
218. Lakshmipathy U, Campbell C (2000) Mitochondrial DNA ligase III function is independent of Xrcc1. Nucleic Acids Res 28:3880–3886
219. Tomkinson AE, Sallmyr A (2013) Structure and function of the DNA ligases encoded by the mammalian LIG3 gene. Gene 531:150–157
220. Lakshmipathy U, Campbell C (2001) Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity. Nucleic Acids Res 29:668–676
221. Simsek D, Furda A, Gao Y, Artus J, Brunet E et al (2011) Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature 471:245–248
222. Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD et al (2014) Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair (Amst) 13:22–31
223. Croteau DL, Rossi ML, Canugovi C, Tian J, Sykora P et al (2012) RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity. Aging Cell 11:456–466
224. De S, Kumari J, Mudgal R, Modi P, Gupta S et al (2012) RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress. J Cell Sci 125:2509–2522
225. Bohr VA (2008) Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance. Trends Biochem Sci 33:609–620
226. Chu WK, Hickson ID (2009) RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer 9:644–654
227. Bachrati CZ, Hickson ID (2008) RecQ helicases: guardian angels of the DNA replication fork. Chromosoma 117:219–233
228. Ouyang KJ, Woo LL, Ellis NA (2008) Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases. Mech Ageing Dev 129:425–440
229. Macris MA, Krejci L, Bussen W, Shimamoto A, Sung P (2006) Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome. DNA Repair (Amst) 5:172–180
230. Suzuki T, Kohno T, Ishimi Y (2009) DNA helicase activity in purified human RECQL4 protein. J Biochem 146:327–335
231. Rossi ML, Ghosh AK, Kulikowicz T, Croteau DL, Bohr VA (2010) Conserved helicase domain of human RecQ4 is required for strand annealing-independent DNA unwinding. DNA Repair (Amst) 9:796–804
232. Yin J, Kwon YT, Varshavsky A, Wang W (2004) RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Hum Mol Genet 13:2421–2430
233. Petkovic M, Dietschy T, Freire R, Jiao R, Stagljar I (2005) The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability. J Cell Sci 118:4261–4269
234. Werner SR, Prahalad AK, Yang J, Hock JM (2006) RECQL4-deficient cells are hypersensitive to oxidative stress/damage: insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochem Biophys Res Commun 345:403–409
235. Woo LL, Futami K, Shimamoto A, Furuichi Y, Frank KM (2006) The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Exp Cell Res 312:3443–3457
236. Burks LM, Yin J, Plon SE (2007) Nuclear import and retention domains in the amino terminus of RECQL4. Gene 391:26–38
237. Singh DK, Karmakar P, Aamann M, Schurman SH, May A et al (2010) The involvement of human RECQL4 in DNA double-strand break repair. Aging Cell 9:358–371
238. Im JS, Ki SH, Farina A, Jung DS, Hurwitz J et al (2009) Assembly of the Cdc45-Mcm2-7-GINS complex in human cells requires the Ctf4/And-1, RecQL4, and Mcm10 proteins. Proc Natl Acad Sci USA 106:15628–15632
239. Schurman SH, Hedayati M, Wang Z, Singh DK, Speina E et al (2009) Direct and indirect roles of RECQL4 in modulating base excision repair capacity. Hum Mol Genet 18:3470–3483
240. Xu X, Rochette PJ, Feyissa EA, Su TV, Liu Y (2009) MCM10 mediates RECQ4 association with MCM2-7 helicase complex during DNA replication. EMBO J 28:3005–3014
241. Thangavel S, Mendoza-Maldonado R, Tissino E, Sidorova JM, Yin J et al (2010) Human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Mol Cell Biol 30:1382–1396
242. Harris JL, Jakob B, Taucher-Scholz G, Dianov GL, Becherel OJ et al (2009) 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 18:4102–4117
243. Rossi MN, Carbone M, Mostocotto C, Mancone C, Tripodi M et al (2009) Mitochondrial localization of PARP-1 requires interaction with mitofilin and is involved in the maintenance of mitochondrial DNA integrity. J Biol Chem 284:31616–31624
244. de Souza-Pinto NC, Harris CC, Bohr VA (2004) p53 functions in the incorporation step in DNA base excision repair in mouse liver mitochondria. Oncogene 23:6559–6568
245. Achanta G, Sasaki R, Feng L, Carew JS, Lu W et al (2005) Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. EMBO J 24:3482–3492
246. Chen D, Yu Z, Zhu Z, Lopez CD (2006) The p53 pathway promotes efficient mitochondrial DNA base excision repair in colorectal cancer cells. Cancer Res 66:3485–3494
247. Osenbroch PO, Auk-Emblem P, Halsne R, Strand J, Forstrom RJ et al (2009) Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells. FEBS J 276:2811–2821
248. Aamann MD, Sorensen MM, Hvitby C, Berquist BR, Muftuoglu M et al (2010) Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane. FASEB J 24:2334–2346
249. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211–212
250. Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES et al (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150–E172
251. Copeland WC (2012) Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol 47:64–74
252. Cohen B, Chinnery PF, Copeland WC (2010) POLG-Related Disorders. In: Pagon R, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (eds) Genereviews at genetests: medical genetics information resource [database online]. University of Washington, Seattle
253. Saneto RP, Naviaux RK (2010) Polymerase gamma disease through the ages. Dev Disabil Res Rev 16:163–174
254. Cohen BH, Naviaux RK (2010) The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 51:364–373
255. Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D et al (1999) Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol 45:54–58
256. Ferrari G, Lamantea E, Donati A, Filosto M, Briem E et al (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128:723–731
257. Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S et al (2006) Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 129:1674–1684
258. Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK (2006) Molecular diagnosis of Alpers syndrome. J Hepatol 45:108–116
259. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN et al (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364:875–882
260. Pagnamenta AT, Taanman JW, Wilson CJ, Anderson NE, Marotta R et al (2006) Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 21:2467–2473
261. Chan SS, Longley MJ, Copeland WC (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
262. Van Goethem G, Luoma P, Rantamaki M, Al Memar A, Kaakkola S et al (2004) POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 63:1251–1257
263. Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT et al (2005) Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77:430–441
264. Chan SS, Longley MJ, Copeland WC (2006) Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphism in mitochondrial disorders. Hum Mol Genet 15:3473–3483
265. Baruffini E, Lodi T, Dallabona C, Puglisi A, Zeviani M 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
266. Lee YS, Johnson KA, Molineux IJ, Yin YW (2010) A single mutation in human mitochondrial DNA polymerase Pol gammaA affects both polymerization and proofreading activities of only the holoenzyme. J Biol Chem 285:28105–28116
267. Stumpf JD, Bailey CM, Spell D, Stillwagon M, Anderson KS 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
268. Szczepanowska K, Foury F (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
269. Graziewicz MA, Longley MJ, Bienstock RJ, Zeviani M, Copeland WC (2004) Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol 11:770–776
270. Ponamarev MV, Longley MJ, Nguyen D, Kunkel TA, Copeland WC (2002) Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis. J Biol Chem 277:15225–15228
271. Suomalainen A, Majander A, Wallin M, Setala K, Kontula K et al (1997) Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease. Neurology 48:1244–1253
272. Van Hove JL, Cunningham V, Rice C, Ringel SP, Zhang Q et al (2009) Finding twinkle in the eyes of a 71-year-old lady: a case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease. Am J Med Genet A 149A:861–867
273. Sarzi E, Goffart S, Serre V, Chretien D, Slama A et al (2007) Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol 62:579–587
274. Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A et al (2007) Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain 130:3032–3040
275. Lonnqvist T, Paetau A, Valanne L, Pihko H (2009) Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132:1553–1562
276. Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C et al (2010) The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology 74:1619–1626
277. Hudson G, Deschauer M, Busse K, Zierz S, Chinnery PF (2005) Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable germline mosaicism. Neurology 64:371–373
278. Karamanlidis G, Nascimben L, Couper GS, Shekar PS, del Monte F et al (2010) Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res 106:1541–1548
279. Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ, Filiano JJ, Perez-Atayde A (1997) Cardiac mitochondrial dysfunction and DNA depletion in children with hypertrophic cardiomyopathy. J Inherit Metab Dis 20:674–680
280. Holmlund T, Farge G, Pande V, Korhonen J, Nilsson L et al (2009) Structure-function defects of the twinkle amino-terminal region in progressive external ophthalmoplegia. Biochim Biophys Acta 1792:132–139
281. Matsushima Y, Kaguni LS (2007) Differential phenotypes of active site and human autosomal dominant progressive external ophthalmoplegia mutations in Drosophila mitochondrial DNA helicase expressed in Schneider cells. J Biol Chem 282:9436–9444
282. Longley MJ, Humble MM, Sharief FS, Copeland WC (2010) Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity. J Biol Chem 285:29690–29702
283. Marin-Garcia J, Goldenthal MJ, Sarnat HB (2000) Kearns-Sayre syndrome with a novel mitochondrial DNA deletion. J Child Neurol 15:555–558
284. Seneca S, Verhelst H, De Meirleir L, Meire F, Ceuterick-De Groote C et al (2001) A new mitochondrial point mutation in the transfer RNA(Leu) gene in a patient with a clinical phenotype resembling Kearns-Sayre syndrome. Arch Neurol 58:1113–1118
285. Houshmand M, Panahi MS, Hosseini BN, Dorraj GH, Tabassi AR (2006) Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external opthalmoplagia. Neurol India 54:182–185
286. Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F et al (2003) Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60:1354–1356
287. Tyynismaa H, Sembongi H, Bokori-Brown M, Granycome C, Ashley N et al (2004) Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. Hum Mol Genet 13:3219–3227
288. Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E et al (2005) Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci USA 102:17687–17692
289. Ronchi D, Di Fonzo A, Lin W, Bordoni A, Liu C et al (2013) Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability. Am J Hum Genet 92:293–300
290. Chisholm KM, Aubert SD, Freese KP, Zakian VA, King MC et al (2012) A genomewide screen for suppressors of Alu-mediated rearrangements reveals a role for PIF1. PLoS One 7:e30748
291. Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P (2003) Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res 31:e61
292. Frahm T, Mohamed SA, Bruse P, Gemund C, Oehmichen M et al (2005) Lack of age-related increase of mitochondrial DNA amount in brain, skeletal muscle and human heart. Mech Ageing Dev 126:1192–1200
293. Wang J, Wilhelmsson H, Graff C, Li H, Oldfors A et al (1999) Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat Genet 21:133–137
294. Li H, Wang J, Wilhelmsson H, Hansson A, Thoren P et al (2000) Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. Proc Natl Acad Sci USA 97:3467–3472
295. Lewis W (2003) Defective mitochondrial DNA replication and NRTIs: pathophysiological implications in AIDS cardiomyopathy. Am J Physiol Heart Circ Physiol 284:H1–H9
296. L’Ecuyer T, Sanjeev S, Thomas R, Novak R, Das L et al (2006) DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol 291:H1273–H1280
297. Lebrecht D, Walker UA (2007) Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7:108–113
298. Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SS et al (2007) Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest 87:326–335
299. Marin-Garcia J, Goldenthal MJ, Moe GW (2001) Mitochondrial pathology in cardiac failure. Cardiovasc Res 49:17–26
300. Karamanlidis G, Nascimben L, Couper GS, Shekar PS, del Monte F et al (2010) Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res 106:1541–1548
301. Sebastiani M, Giordano C, Nediani C, Travaglini C, Borchi E et al (2007) Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J Am Coll Cardiol 50:1362–1369
302. Garnier A, Zoll J, Fortin D, N’Guessan B, Lefebvre F et al (2009) Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II. Circ Heart Fail 2:342–350
303. Kajander OA, Karhunen PJ, Holt IJ, Jacobs HT (2001) Prominent mitochondrial DNA recombination intermediates in human heart muscle. EMBO Rep 2:1007–1012
304. Pohjoismaki JL, Goffart S, Taylor RW, Turnbull DM, Suomalainen A et al (2010) Developmental and pathological changes in the human cardiac muscle mitochondrial DNA organization, replication and copy number. PLoS One 5:e10426
305. Pohjoismaki JL, Goffart S (2011) Of circles, forks and humanity: topological organisation and replication of mammalian mitochondrial DNA. BioEssays 33:290–299
306. Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T et al (2005) Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 112:683–690
307. Tanaka A, Ide T, Fujino T, Onitsuka K, Ikeda M et al (2013) The overexpression of Twinkle helicase ameliorates the progression of cardiac fibrosis and heart failure in pressure overload model in mice. PLoS One 8:e67642
308. Pohjoismaki JL, Williams SL, Boettger T, Goffart S, Kim J et al (2013) Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species. Proc Natl Acad Sci USA 110:19408–19413
309. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–423
310. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K et al (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484
311. Pohjoismaki JL, Goffart S, Spelbrink JN (2011) Replication stalling by catalytically impaired Twinkle induces mitochondrial DNA rearrangements in cultured cells. Mitochondrion 11:630–634