Skip to main content

Advertisement

Log in

Mitochondrial DNA maintenance: an appraisal

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Mitochondria play a crucial role in a variety of cellular processes ranging from energy metabolism, generation of reactive oxygen species (ROS), and Ca2+ handling to stress responses, cell survival, and death. Malfunction of the organelle may contribute to the pathogenesis of neuromuscular disorders, cancer, premature aging, and cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Mitochondria are unique as they contain their own genome organized into DNA–protein complexes, so-called mitochondrial nucleoids, along with multiprotein machineries, which promote mitochondrial DNA (mtDNA) replication, transcription, and repair. Although the organelle possesses almost all known nuclear DNA repair pathways, including base excision repair, mismatch repair, and recombinational repair, the proximity of mtDNA to the main sites of ROS production and the lack of protective histones may result in increased susceptibility to oxidative stress and other types of mtDNA damage. Defects in the components of these highly organized machineries, which mediate mtDNA maintenance (replication and repair), may result in accumulation of point mutations and/or deletions in mtDNA and decreased mtDNA copy number impairing mitochondrial function. This review will focus on the mechanisms of mtDNA maintenance with emphasis on the proteins implicated in these processes and their functional role in various disease conditions and aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cadenas S, Aragones J, Landazuri MO (2010) Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease. Cardiovasc Res 88:219–228

    Article  CAS  PubMed  Google Scholar 

  2. Rosca MG, Hoppel CL (2010) Mitochondria in heart failure. Cardiovasc Res 88:40–50

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Wong LJ (2010) Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 16:154–162

    Article  PubMed  Google Scholar 

  4. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159

    Article  CAS  PubMed  Google Scholar 

  5. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Clayton DA (1991) Replication and transcription of vertebrate mitochondrial DNA. Annu Rev Cell Biol 7:453–478

    Article  CAS  PubMed  Google Scholar 

  7. Chen XJ, Butow RA (2005) The organization and inheritance of the mitochondrial genome. Nat Rev Genet 6:815–825

    Article  CAS  PubMed  Google Scholar 

  8. Holt IJ (2009) Mitochondrial DNA replication and repair: all a flap. Trends Biochem Sci 34:358–365

    Article  CAS  PubMed  Google Scholar 

  9. McKinney EA, Oliveira MT (2013) Replicating animal mitochondrial DNA. Genet Mol Biol 36:308–315

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Kucej M, Butow RA (2007) Evolutionary tinkering with mitochondrial nucleoids. Trends Cell Biol 17:586–592

    Article  CAS  PubMed  Google Scholar 

  11. Spelbrink JN (2010) Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life 62:19–32

    CAS  PubMed  Google Scholar 

  12. Bogenhagen DF (2012) Mitochondrial DNA nucleoid structure. Biochim Biophys Acta 1819:914–920

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  14. Wanrooij S, Falkenberg M (2010) The human mitochondrial replication fork in health and disease. Biochim Biophys Acta 1797:1378–1388

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  16. Calvo SE, Mootha VK (2010) The mitochondrial proteome and human disease. Annu Rev Genomics Hum Genet 11:25–44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138:628–644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Schmidt O, Pfanner N, Meisinger C (2010) Mitochondrial protein import: from proteomics to functional mechanisms. Nat Rev Mol Cell Biol 11:655–667

    Article  CAS  PubMed  Google Scholar 

  19. Ryan MT, Hoogenraad NJ (2007) Mitochondrial-nuclear communications. Annu Rev Biochem 76:701–722

    Article  CAS  PubMed  Google Scholar 

  20. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Kasiviswanathan R, Collins TR, Copeland WC (2012) The interface of transcription and DNA replication in the mitochondria. Biochim Biophys Acta 1819:970–978

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M (2004) Reconstitution of a minimal mtDNA replisome in vitro. EMBO J 23:2423–2429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Copeland WC, Longley MJ (2014) Mitochondrial genome maintenance in health and disease. DNA Repair (Amst) 19:190–198

    Article  CAS  Google Scholar 

  24. Shutt TE, Gray MW (2006) Bacteriophage origins of mitochondrial replication and transcription proteins. Trends Genet 22:90–95

    Article  CAS  PubMed  Google Scholar 

  25. Kaguni LS (2004) DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 73:293–320

    Article  CAS  PubMed  Google Scholar 

  26. Graziewicz MA, Longley MJ, Copeland WC (2006) DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev 106:383–405

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  36. Bogenhagen DF, Rousseau D, Burke S (2008) The layered structure of human mitochondrial DNA nucleoids. J Biol Chem 283:3665–3675

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    PubMed Central  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  43. Fisher RP, Clayton DA (1988) Purification and characterization of human mitochondrial transcription factor 1. Mol Cell Biol 8:3496–3509

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Parisi MA, Clayton DA (1991) Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252:965–969

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Patel SS, Donmez I (2006) Mechanisms of helicases. J Biol Chem 281:18265–18268

    Article  CAS  PubMed  Google Scholar 

  57. Singleton MR, Dillingham MS, Wigley DB (2007) Structure and mechanism of helicases and nucleic acid translocases. Annu Rev Biochem 76:23–50

    Article  CAS  PubMed  Google Scholar 

  58. Dillingham MS (2011) Superfamily I helicases as modular components of DNA-processing machines. Biochem Soc Trans 39:413–423

    Article  CAS  PubMed  Google Scholar 

  59. Hubscher U (2009) DNA replication fork proteins. Methods Mol Biol 521:19–33

    Article  CAS  PubMed  Google Scholar 

  60. Bernstein KA, Gangloff S, Rothstein R (2010) The RecQ DNA helicases in DNA repair. Annu Rev Genet 44:393–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Wu Y (2012) Unwinding and rewinding: double faces of helicase? J Nucleic Acids 2012:140601

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  64. Fanning E, Knippers R (1992) Structure and function of simian virus 40 large tumor antigen. Annu Rev Biochem 61:55–85

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Morris PD, Raney KD (1999) DNA helicases displace streptavidin from biotin-labeled oligonucleotides. Biochemistry 38:5164–5171

    Article  CAS  PubMed  Google Scholar 

  68. Patel SS, Picha KM (2000) Structure and function of hexameric helicases. Annu Rev Biochem 69:651–697

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  71. Ziebarth TD, Farr CL, Kaguni LS (2007) Modular architecture of the hexameric human mitochondrial DNA helicase. J Mol Biol 367:1382–1391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  87. Xu X, Liu Y (2009) Dual DNA unwinding activities of the Rothmund-Thomson syndrome protein, RECQ4. EMBO J 28:568–577

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Masuda-Sasa T, Imamura O, Campbell JL (2006) Biochemical analysis of human Dna2. Nucleic Acids Res 34:1865–1875

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Boule JB, Zakian VA (2006) Roles of Pif1-like helicases in the maintenance of genomic stability. Nucleic Acids Res 34:4147–4153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Bochman ML, Sabouri N, Zakian VA (2010) Unwinding the functions of the Pif1 family helicases. DNA Repair (Amst) 9:237–249

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Lahaye A, Stahl H, Thines-Sempoux D, Foury F (1991) PIF1: a DNA helicase in yeast mitochondria. EMBO J 10:997–1007

    PubMed Central  CAS  PubMed  Google Scholar 

  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

    PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Mateyak MK, Zakian VA (2006) Human PIF helicase is cell cycle regulated and associates with telomerase. Cell Cycle 5:2796–2804

    Article  CAS  PubMed  Google Scholar 

  115. Futami K, Shimamoto A, Furuichi Y (2007) Mitochondrial and nuclear localization of human Pif1 helicase. Biol Pharm Bull 30:1685–1692

    Article  CAS  PubMed  Google Scholar 

  116. Huang Y, Zhang DH, Zhou JQ (2006) Characterization of ATPase activity of recombinant human Pif1. Acta Biochim Biophys Sin (Shanghai) 38:335–341

    Article  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Halliwell B, Gutteridge JM (1984) Free radicals, lipid peroxidation, and cell damage. Lancet 2:1095

    Article  CAS  PubMed  Google Scholar 

  123. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Cadet J, Douki T, Ravanat JL (2010) Oxidatively generated base damage to cellular DNA. Free Radic Biol Med 49:9–21

    Article  CAS  PubMed  Google Scholar 

  126. Roede JR, Jones DP (2010) Reactive species and mitochondrial dysfunction: mechanistic significance of 4-hydroxynonenal. Environ Mol Mutagen 51:380–390

    CAS  PubMed  Google Scholar 

  127. Yin H, Xu L, Porter NA (2011) Free radical lipid peroxidation: mechanisms and analysis. Chem Rev 111:5944–5972

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Stumpf JD, Copeland WC (2011) Mitochondrial DNA replication and disease: insights from DNA polymerase gamma mutations. Cell Mol Life Sci 68:219–233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  131. Stumpf JD, Saneto RP, Copeland WC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5:a011395

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Larsson NG, Clayton DA (1995) Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet 29:151–178

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Niranjan BG, Bhat NK, Avadhani NG (1982) Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science 215:73–75

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. Cline SD (2012) Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim Biophys Acta 1819:979–991

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  144. Singer TP, Ramsay RR (1990) Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett 274:1–8

    Article  CAS  PubMed  Google Scholar 

  145. Bandy B, Davison AJ (1990) Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 8:523–539

    Article  CAS  PubMed  Google Scholar 

  146. De Bont R, van Larebeke N (2004) Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19:169–185

    Article  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  153. Cadet J, Douki T, Ravanat JL (2011) Measurement of oxidatively generated base damage in cellular DNA. Mutat Res 711:3–12

    Article  CAS  PubMed  Google Scholar 

  154. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  156. Nakamura J, Swenberg JA (1999) Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res 59:2522–2526

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9:619–631

    CAS  PubMed  Google Scholar 

  160. McKinnon PJ, Caldecott KW (2007) DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 8:37–55

    Article  CAS  PubMed  Google Scholar 

  161. Kasparek TR, Humphrey TC (2011) DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol 22:886–897

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  164. Liu P, Demple B (2010) DNA repair in mammalian mitochondria: much more than we thought? Environ Mol Mutagen 51:417–426

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  166. Sykora P, Wilson DM 3rd, Bohr VA (2012) Repair of persistent strand breaks in the mitochondrial genome. Mech Ageing Dev 133:169–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  174. Larsen NB, Rasmussen M, Rasmussen LJ (2005) Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion 5:89–108

    Article  CAS  PubMed  Google Scholar 

  175. Stuart JA, Brown MF (2006) Mitochondrial DNA maintenance and bioenergetics. Biochim Biophys Acta 1757:79–89

    Article  CAS  PubMed  Google Scholar 

  176. Druzhyna NM, Wilson GL, LeDoux SP (2008) Mitochondrial DNA repair in aging and disease. Mech Ageing Dev 129:383–390

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  177. Chen XJ (2013) Mechanism of homologous recombination and implications for aging-related deletions in mitochondrial DNA. Microbiol Mol Biol Rev 77:476–496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  180. LeDoux SP, Driggers WJ, Hollensworth BS, Wilson GL (1999) Repair of alkylation and oxidative damage in mitochondrial DNA. Mutat Res 434:149–159

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  189. Dizdaroglu M (2005) Base-excision repair of oxidative DNA damage by DNA glycosylases. Mutat Res 591:45–59

    Article  CAS  PubMed  Google Scholar 

  190. Huffman JL, Sundheim O, Tainer JA (2005) DNA base damage recognition and removal: new twists and grooves. Mutat Res 577:55–76

    Article  CAS  PubMed  Google Scholar 

  191. Dodson ML, Lloyd RS (2002) Mechanistic comparisons among base excision repair glycosylases. Free Radic Biol Med 32:678–682

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  205. Ide H, Kotera M (2004) Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull 27:480–485

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  207. Demple B, Sung JS (2005) Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair (Amst) 4:1442–1449

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  212. Tahbaz N, Subedi S, Weinfeld M (2012) Role of polynucleotide kinase/phosphatase in mitochondrial DNA repair. Nucleic Acids Res 40:3484–3495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  218. Lakshmipathy U, Campbell C (2000) Mitochondrial DNA ligase III function is independent of Xrcc1. Nucleic Acids Res 28:3880–3886

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  219. Tomkinson AE, Sallmyr A (2013) Structure and function of the DNA ligases encoded by the mammalian LIG3 gene. Gene 531:150–157

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  225. Bohr VA (2008) Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance. Trends Biochem Sci 33:609–620

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  226. Chu WK, Hickson ID (2009) RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer 9:644–654

    Article  CAS  PubMed  Google Scholar 

  227. Bachrati CZ, Hickson ID (2008) RecQ helicases: guardian angels of the DNA replication fork. Chromosoma 117:219–233

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  230. Suzuki T, Kohno T, Ishimi Y (2009) DNA helicase activity in purified human RECQL4 protein. J Biochem 146:327–335

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  236. Burks LM, Yin J, Plon SE (2007) Nuclear import and retention domains in the amino terminus of RECQL4. Gene 391:26–38

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  251. Copeland WC (2012) Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol 47:64–74

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Google Scholar 

  253. Saneto RP, Naviaux RK (2010) Polymerase gamma disease through the ages. Dev Disabil Res Rev 16:163–174

    Article  PubMed  Google Scholar 

  254. Cohen BH, Naviaux RK (2010) The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 51:364–373

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  258. Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK (2006) Molecular diagnosis of Alpers syndrome. J Hepatol 45:108–116

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  275. Lonnqvist T, Paetau A, Valanne L, Pihko H (2009) Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132:1553–1562

    Article  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  283. Marin-Garcia J, Goldenthal MJ, Sarnat HB (2000) Kearns-Sayre syndrome with a novel mitochondrial DNA deletion. J Child Neurol 15:555–558

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  295. Lewis W (2003) Defective mitochondrial DNA replication and NRTIs: pathophysiological implications in AIDS cardiomyopathy. Am J Physiol Heart Circ Physiol 284:H1–H9

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  297. Lebrecht D, Walker UA (2007) Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7:108–113

    Article  CAS  PubMed  Google Scholar 

  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

    PubMed Central  CAS  PubMed  Google Scholar 

  299. Marin-Garcia J, Goldenthal MJ, Moe GW (2001) Mitochondrial pathology in cardiac failure. Cardiovasc Res 49:17–26

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  303. Kajander OA, Karhunen PJ, Holt IJ, Jacobs HT (2001) Prominent mitochondrial DNA recombination intermediates in human heart muscle. EMBO Rep 2:1007–1012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  305. Pohjoismaki JL, Goffart S (2011) Of circles, forks and humanity: topological organisation and replication of mammalian mitochondrial DNA. BioEssays 33:290–299

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to José Marín-García.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akhmedov, A.T., Marín-García, J. Mitochondrial DNA maintenance: an appraisal. Mol Cell Biochem 409, 283–305 (2015). https://doi.org/10.1007/s11010-015-2532-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-015-2532-x

Keywords

Navigation