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Review Articles

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

ORCID Icon &
Pages 509-524 | Received 07 Feb 2020, Accepted 31 Aug 2020, Published online: 24 Sep 2020

References

  • Agaronyan K, Morozov YI, Anikin M, Temiakov D. 2015. Mitochondrial biology. Replication-transcription switch in human mitochondria. Science. 347(6221):548–551.
  • Alam TI, Kanki T, Muta T, Ukaji K, Abe Y, Nakayama H, Takio K, Hamasaki N, Kang D. 2003. Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Res. 31(6):1640–1645.
  • Al-Behadili A, Uhler JP, Berglund AK, Peter B, Doimo M, Reyes A, Wanrooij S, Zeviani M, Falkenberg M. 2018. A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL. Nucleic Acids Res. 46(18):9471–9483.
  • Amalric F, Merkel C, Gelfand R, Attardi G. 1978. Fractionation of mitochondrial RNA from HeLa cells by high-resolution electrophoresis under strongly denaturing conditions. J Mol Biol. 118(1):1–25.
  • Bailey LJ, Cluett TJ, Reyes A, Prolla TA, Poulton J, Leeuwenburgh C, Holt IJ. 2009. Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA. Nucleic Acids Res. 37(7):2327–2335.
  • Berk AJ, Clayton DA. 1974. Mechanism of mitochondrial DNA replication in mouse L-cells: asynchronous replication of strands, segregation of circular daughter molecules, aspects of topology and turnover of an initiation sequence. J Mol Biol. 86(4):801–824.
  • Bogenhagen D, Clayton DA. 1978. Mechanism of mitochondrial DNA replication in mouse L-cells: kinetics of synthesis and turnover of the initiation sequence. J Mol Biol. 119(1):49–68.
  • Bogenhagen DF, Rousseau D, Burke S. 2008. The layered structure of human mitochondrial DNA nucleoids. J Biol Chem. 283(6):3665–3675.
  • Brown GG, Gadaleta G, Pepe G, Saccone C, Sbisa E. 1986. Structural conservation and variation in the D-loop-containing region of vertebrate mitochondrial DNA. J Mol Biol. 192(3):503–511.
  • Brown TA, Cecconi C, Tkachuk AN, Bustamante C, Clayton DA. 2005. Replication of mitochondrial DNA occurs by strand displacement with alternative light-strand origins, not via a strand-coupled mechanism. Genes Dev. 19(20):2466–2476.
  • Calvo SE, Clauser KR, Mootha VK. 2016. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44(D1):D1251–D1257.
  • Carrodeguas JA, Pinz KG, Bogenhagen DF. 2002. DNA binding properties of human pol gammaB. J Biol Chem. 277(51):50008–50014.
  • Cerritelli SM, Crouch RJ. 2009. Ribonuclease H: the enzymes in eukaryotes. Febs J. 276(6):1494–1505.
  • Cerritelli SM, Frolova EG, Feng C, Grinberg A, Love PE, Crouch RJ. 2003. Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice. Mol Cell. 11(3):807–815.
  • Chang DD, Clayton DA. 1985. Priming of human mitochondrial DNA replication occurs at the light-strand promoter. Proc Natl Acad Sci USA. 82(2):351–355.
  • Chang DD, Clayton DA. 1987. A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. EMBO J. 6(2):409–417.
  • Chang DD, Hauswirth WW, Clayton DA. 1985. Replication priming and transcription initiate from precisely the same site in mouse mitochondrial DNA. EMBO J. 4(6):1559–1567.
  • Clayton DA. 1991. Replication and transcription of vertebrate mitochondrial DNA. Annu Rev Cell Biol. 7:453–478.
  • Cortopassi GA, Arnheim N. 1990. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18(23):6927–6933.
  • Dalla Rosa I, Zhang H, Khiati S, Wu X, Pommier Y. 2017. Transcription profiling suggests that mitochondrial topoisomerase IB acts as a topological barrier and regulator of mitochondrial DNA transcription. J Biol Chem. 292(49):20162–20172.
  • Del Dotto V, Ullah F, Di Meo I, Magini P, Gusic M, Maresca A, Caporali L, Palombo F, Tagliavini F, Baugh EH, et al. 2020. SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder. J Clin Invest. 130(1):108–125.
  • Doda JN, Wright CT, Clayton DA. 1981. Elongation of displacement-loop strands in human and mouse mitochondrial DNA is arrested near specific template sequences. Proc Natl Acad Sci USA. 78(10):6116–6120.
  • Douarre C, Sourbier C, Dalla Rosa I, Brata Das B, Redon CE, Zhang H, Neckers L, Pommier Y. 2012. Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism. PLoS One. 7(7):e41094.
  • Fan L, Kim S, Farr CL, Schaefer KT, Randolph KM, Tainer JA, Kaguni LS. 2006. A novel processive mechanism for DNA synthesis revealed by structure, modeling and mutagenesis of the accessory subunit of human mitochondrial DNA polymerase. J Mol Biol. 358(5):1229–1243.
  • Farge G, Falkenberg M. 2019. Organization of DNA in mammalian mitochondria. Int J Mol Sci. 20(11):2770.
  • Farge G, Laurens N, Broekmans OD, van den Wildenberg SM, Dekker LC, Gaspari M, Gustafsson CM, Peterman EJ, Falkenberg M, Wuite GJ. 2012. Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A. Nat Commun. 3:1013.
  • Farge G, Mehmedovic M, Baclayon M, van den Wildenberg SM, Roos WH, Gustafsson CM, Wuite GJ, Falkenberg M. 2014. In vitro-reconstituted nucleoids can block mitochondrial DNA replication and transcription. Cell Rep. 8(1):66–74.
  • Farr CL, Wang Y, Kaguni LS. 1999. Functional interactions of mitochondrial DNA polymerase and single-stranded DNA-binding protein. Template-primer DNA binding and initiation and elongation of DNA strand synthesis. J Biol Chem. 274(21):14779–14785.
  • Fish J, Raule N, Attardi G. 2004. Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis. Science. 306(5704):2098–2101.
  • Fuste JM, Wanrooij S, Jemt E, Granycome CE, Cluett TJ, Shi Y, Atanassova N, Holt IJ, Gustafsson CM, Falkenberg M. 2010. Mitochondrial RNA polymerase is needed for activation of the origin of light-strand DNA replication. Mol Cell. 37(1):67–78.
  • Garcia-Gomez S, Reyes A, Martinez-Jimenez MI, Chocron ES, Mouron S, Terrados G, Powell C, Salido E, Mendez J, Holt IJ, et al. 2013. PrimPol, an archaic primase/polymerase operating in human cells. Mol Cell. 52(4):541–553.
  • Gillum AM, Clayton DA. 1979. Mechanism of mitochondrial DNA replication in mouse L-cells: RNA priming during the initiation of heavy-strand synthesis. J Mol Biol. 135(2):353–368.
  • Gray H, Wong TW. 1992. Purification and identification of subunit structure of the human mitochondrial DNA polymerase. J Biol Chem. 267(9):5835–5841.
  • Gustafson MA, McCormick EM, Perera L, Longley MJ, Bai R, Kong J, Dulik M, Shen L, Goldstein AC, McCormack SE, et al. 2019. Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes. PLoS One. 14(9):e0221829.
  • Gustafsson CM, Falkenberg M, Larsson NG. 2016. Maintenance and Expression of Mammalian Mitochondrial DNA. Annu Rev Biochem. 85:133–160.
  • Han S, Udeshi ND, Deerinck TJ, Svinkina T, Ellisman MH, Carr SA, Ting AY. 2017. Proximity biotinylation as a method for mapping proteins associated with mtDNA in living cells. Cell Chem Biol. 24(3):404–414.
  • Hance N, Ekstrand MI, Trifunovic A. 2005. Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. Hum Mol Genet. 14(13):1775–1783.
  • Hayashi J, Ohta S, Kikuchi A, Takemitsu M, Goto Y, Nonaka I. 1991. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc Natl Acad Sci USA. 88(23):10614–10618.
  • He J, Cooper HM, Reyes A, Di Re M, Kazak L, Wood SR, Mao CC, Fearnley IM, Walker JE, Holt IJ. 2012. Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit. Nucleic Acids Res. 40(13):6097–6108.
  • Hillen HS, Parshin AV, Agaronyan K, Morozov YI, Graber JJ, Chernev A, Schwinghammer K, Urlaub H, Anikin M, Cramer P, et al. 2017. Mechanism of transcription anti-termination in human mitochondria. Cell. 171(5):1082–1093.
  • Hillen HS, Temiakov D, Cramer P. 2018. Structural basis of mitochondrial transcription. Nat Struct Mol Biol. 25(9):754–765.
  • Holmes JB, Akman G, Wood SR, Sakhuja K, Cerritelli SM, Moss C, Bowmaker MR, Jacobs HT, Crouch RJ, Holt IJ. 2015. Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication. Proc Natl Acad Sci USA. 112(30):9334–9339.
  • Holt IJ, Jacobs HT. 2014. Unique features of DNA replication in mitochondria: a functional and evolutionary perspective. Bioessays. 36(11):1024–1031.
  • Holt IJ, Lorimer HE, Jacobs HT. 2000. Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. Cell. 100(5):515–524.
  • Hudson B, Vinograd J. 1967. Catenated circular DNA molecules in HeLa cell mitochondria. Nature. 216(5116):647–652.
  • Humble MM, Young MJ, Foley JF, Pandiri AR, Travlos GS, Copeland WC. 2013. Polg2 is essential for mammalian embryogenesis and is required for mtDNA maintenance. Hum Mol Genet. 22(5):1017–1025.
  • Jemt E, Persson O, Shi Y, Mehmedovic M, Uhler JP, Davila Lopez M, Freyer C, Gustafsson CM, Samuelsson T, Falkenberg M. 2015. Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element. Nucleic Acids Res. 43(19):9262–9275.
  • Jiang S, Koolmeister C, Misic J, Siira S, Kuhl I, Silva Ramos E, Miranda M, Jiang M, Posse V, Lytovchenko O, et al. 2019. TEFM regulates both transcription elongation and RNA processing in mitochondria. EMBO Rep. 20(6):e48101.
  • Kang D, Miyako K, Kai Y, Irie T, Takeshige K. 1997. In vivo determination of replication origins of human mitochondrial DNA by ligation-mediated polymerase chain reaction. J Biol Chem. 272(24):15275–15279.
  • Kao WW, Mai SH, Chou KL, Ebert J. 1983. Mechanism for the regulation of post-translational modifications of procollagens synthesized by matrix-free cells from chick embryos. J Biol Chem. 258(12):7779–7787.
  • Kaufman BA, Durisic N, Mativetsky JM, Costantino S, Hancock MA, Grutter P, Shoubridge EA. 2007. The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol Biol Cell. 18(9):3225–3236.
  • Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, Keranen S, Peltonen L, Suomalainen A. 2000. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science. 289(5480):782–785.
  • Kaur P, Longley MJ, Pan H, Wang H, Copeland WC. 2018. Single-molecule DREEM imaging reveals DNA wrapping around human mitochondrial single-stranded DNA binding protein. Nucleic Acids Res. 46(21):11287–11302.
  • Kiss T, Filipowicz W. 1992. Evidence against a mitochondrial location of the 7-2/MRP RNA in mammalian cells. Cell. 70(1):11–16.
  • Kiss T, Marshallsay C, Filipowicz W. 1992. 7-2/MRP RNAs in plant and mammalian cells: association with higher order structures in the nucleolus. EMBO J. 11(10):3737–3746.
  • Kogoma T, von Meyenburg K. 1983. The origin of replication, oriC, and the dnaA protein are dispensable in stable DNA replication (sdrA) mutants of Escherichia coli K-12. EMBO J. 2(3):463–468.
  • 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(49):48627–48632.
  • Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH, Nilsson L, Falkenberg M. 2008. Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia. J Mol Biol. 377(3):691–705.
  • Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. 2004. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J. 23(12):2423–2429.
  • Kornblum C, Nicholls TJ, Haack TB, Scholer S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, et al. 2013. Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet. 45(2):214–219.
  • Krasich R, Copeland WC. 2017. DNA polymerases in the mitochondria: a critical review of the evidence. Front Biosci. 22:692–709.
  • Kukat C, Davies KM, Wurm CA, Spahr H, Bonekamp NA, Kuhl I, Joos F, Polosa PL, Park CB, Posse V, et al. 2015. Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. Proc Natl Acad Sci USA. 112(36):11288–11293.
  • Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG, Jakobs S. 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(33):13534–13539.
  • Lee DY, Clayton DA. 1997. RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication. Genes Dev. 11(5):582–592.
  • Lee DY, Clayton DA. 1998. Initiation of mitochondrial DNA replication by transcription and R-loop processing. J Biol Chem. 273(46):30614–30621.
  • Lewis JS, Jergic S, Dixon NE. 2016. The E. coli DNA replication fork. Enzymes. 39:31–88.
  • Lima WF, Rose JB, Nichols JG, Wu H, Migawa MT, Wyrzykiewicz TK, Siwkowski AM, Crooke ST. 2007. Human RNase H1 discriminates between subtle variations in the structure of the heteroduplex substrate. Mol Pharmacol. 71(1):83–91.
  • Lohman TM, Ferrari ME. 1994. Escherichia coli single-stranded DNA-binding protein: multiple DNA-binding modes and cooperativities. Annu Rev Biochem. 63:527–570.
  • 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(42):38555–38562.
  • Macao B, Uhler JP, Siibak T, Zhu X, Shi Y, Sheng W, Olsson M, Stewart JB, Gustafsson CM, Falkenberg M. 2015. The exonuclease activity of DNA polymerase gamma is required for ligation during mitochondrial DNA replication. Nat Commun. 6:7303.
  • Martens PA, Clayton DA. 1979. Mechanism of mitochondrial DNA replication in mouse L-cells: localization and sequence of the light-strand origin of replication. J Mol Biol. 135(2):327–351.
  • Matic S, Jiang M, Nicholls TJ, Uhler JP, Dirksen-Schwanenland C, Polosa PL, Simard ML, Li X, Atanassov I, Rackham O, et al. 2018. Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria. Nat Commun. 9(1):1202.
  • Mignotte B, Barat M, Mounolou JC. 1985. Characterization of a mitochondrial protein binding to single-stranded DNA. Nucleic Acids Res. 13(5):1703–1716.
  • Miralles Fuste J, Shi Y, Wanrooij S, Zhu X, Jemt E, Persson O, Sabouri N, Gustafsson CM, Falkenberg M. 2014. In vivo occupancy of mitochondrial single-stranded DNA binding protein supports the strand displacement mode of DNA replication. PLoS Genet. 10(12):e1004832.
  • Nicholls TJ, Minczuk M. 2014. In D-loop: 40 years of mitochondrial 7S DNA. Exp Gerontol. 56:175–181.
  • Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, Basu S, Hoberg E, Turnbull DM, Chinnery PF, Larsson NG, et al. 2018. Topoisomerase 3alpha Is required for decatenation and segregation of human mtDNA. Mol Cell. 69(1):9–23.
  • Nicholls TJ, Zsurka G, Peeva V, Scholer S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, et al. 2014. Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Hum Mol Genet. 23(23):6147–6162.
  • Nissanka N, Minczuk M, Moraes CT. 2019. Mechanisms of mitochondrial DNA deletion formation. Trends Genet. 35(3):235–244.
  • Ogawa T, Pickett GG, Kogoma T, Kornberg A. 1984. RNase H confers specificity in the dnaA-dependent initiation of replication at the unique origin of the Escherichia coli chromosome in vivo and in vitro. Proc Natl Acad Sci USA. 81(4):1040–1044.
  • Pereira F, Soares P, Carneiro J, Pereira L, Richards MB, Samuels DC, Amorim A. 2008. Evidence for variable selective pressures at a large secondary structure of the human mitochondrial DNA control region. Mol Biol E. 25(12):2759–2770.
  • Persson O, Muthukumar Y, Basu S, Jenninger L, Uhler JP, Berglund AK, McFarland R, Taylor RW, Gustafsson CM, Larsson E, et al. 2019. Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions. Nat Commun. 10(1):759.
  • Pham XH, Farge G, Shi Y, Gaspari M, Gustafsson CM, Falkenberg M. 2006. Conserved sequence box II directs transcription termination and primer formation in mitochondria. J Biol Chem. 281(34):24647–24652.
  • Phillips AF, Millet AR, Tigano M, Dubois SM, Crimmins H, Babin L, Charpentier M, Piganeau M, Brunet E, Sfeir A. 2017. Single-molecule analysis of mtDNA replication uncovers the basis of the common deletion. Mol Cell. 65(3):527–538.
  • Piro-Megy C, Sarzi E, Tarres-Sole A, Pequignot M, Hensen F, Quiles M, Manes G, Chakraborty A, Senechal A, Bocquet B, et al. 2019. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy. J Clin Invest. 130(1):143–156.
  • Pohjoismaki JL, Goffart S, Spelbrink JN. 2011. Replication stalling by catalytically impaired Twinkle induces mitochondrial DNA rearrangements in cultured cells. Mitochondrion. 11(4):630–634.
  • Posse V, Al-Behadili A, Uhler JP, Clausen AR, Reyes A, Zeviani M, Falkenberg M, Gustafsson CM. 2019. RNase H1 directs origin-specific initiation of DNA replication in human mitochondria. PLoS Genet. 15(1):e1007781.
  • Posse V, Shahzad S, Falkenberg M, Hallberg BM, Gustafsson CM. 2015. TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. Nucleic Acids Res. 43(5):2615–2624.
  • Qian Y, Johnson KA. 2017. The human mitochondrial single-stranded DNA-binding protein displays distinct kinetics and thermodynamics of DNA binding and exchange. J Biol Chem. 292(31):13068–13084.
  • Rahman S, Copeland WC. 2019. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 15(1):40–52.
  • Ravichandran V, Vasquez GB, Srivastava S, Verma M, Petricoin E, Lubell J, Sriram RD, Barker PE, Gilliland GL. 2004. Data standards for proteomics: mitochondrial two-dimensional polyacrylamide gel electrophoresis data as a model system. Mitochondrion. 3(6):327–336.
  • Reyes A, Kazak L, Wood SR, Yasukawa T, Jacobs HT, Holt IJ. 2013. Mitochondrial DNA replication proceeds via a ‘bootlace’ mechanism involving the incorporation of processed transcripts. Nucleic Acids Res. 41(11):5837–5850.
  • Reyes A, Melchionda L, Nasca A, Carrara F, Lamantea E, Zanolini A, Lamperti C, Fang M, Zhang J, Ronchi D, et al. 2015. RNASEH1 mutations impair mtDNA replication and cause adult-onset mitochondrial encephalomyopathy. Am J Hum Genet. 97(1):186–193.
  • Robberson DL, Kasamatsu H, Vinograd J. 1972. Replication of mitochondrial DNA. Circular replicative intermediates in mouse L cells. Proc Natl Acad Sci USA. 69(3):737–741.
  • Roberti M, Musicco C, Polosa PL, Milella F, Gadaleta MN, Cantatore P. 1998. Multiple protein-binding sites in the TAS-region of human and rat mitochondrial DNA. Biochem Biophys Res Commun. 243(1):36–40.
  • Samuels DC, Schon EA, Chinnery PF. 2004. Two direct repeats cause most human mtDNA deletions. Trends Genet. 20(9):393–398.
  • Sarbajna S, West SC. 2014. Holliday junction processing enzymes as guardians of genome stability. Trends Biochem Sci. 39(9):409–419.
  • Satoh M, Kuroiwa T. 1991. Organization of multiple nucleoids and DNA molecules in mitochondria of a human cell. Exp Cell Res. 196(1):137–140.
  • Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. 1989. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science. 244(4902):346–349.
  • Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC. 1989. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci USA. 86(20):7952–7956.
  • Singh B, Li X, Owens KM, Vanniarajan A, Liang P, Singh KK. 2015. Human REV3 DNA polymerase zeta localizes to mitochondria and protects the mitochondrial genome. PLoS One. 10(10):e0140409.
  • Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, 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(3):223–231.
  • Srivastava S, Moraes CT. 2005. Double-strand breaks of mouse muscle mtDNA promote large deletions similar to multiple mtDNA deleetions in humans. Hum Mol Genet. 14(7):893–902.
  • Sun Q, Csorba T, Skourti-Stathaki K, Proudfoot NJ, Dean C. 2013. R-loop stabilization represses antisense transcription at the Arabidopsis FLC locus. Science. 340(6132):619–621.
  • Sykora P, Wilson DM, 3rd, Bohr VA. 2013. Base excision repair in the mammalian brain: implication for age related neurodegeneration. Mech Ageing Dev. 134(10):440–448.
  • Szczesny RJ, Hejnowicz MS, Steczkiewicz K, Muszewska A, Borowski LS, Ginalski K, Dziembowski A. 2013. Identification of a novel human mitochondrial endo-/exonuclease Ddk1/c20orf72 necessary for maintenance of proper 7S DNA levels. Nucleic Acids Res. 41(5):3144–3161.
  • Tapper DP, Clayton DA. 1981. Mechanism of replication of human mitochondrial DNA. Localization of the 5′ ends of nascent daughter strands. J Biol Chem. 256(10):5109–5115.
  • Tiranti V, Rocchi M, DiDonato S, Zeviani M. 1993. Cloning of human and rat cDNAs encoding the mitochondrial single-stranded DNA-binding protein (SSB). Gene. 126(2):219–225.
  • Topper JN, Bennett JL, Clayton DA. 1992. A role for RNAase MRP in mitochondrial RNA processing. Cell. 70(1):16–20.
  • Torregrosa-Munumer R, Hangas A, Goffart S, Blei D, Zsurka G, Griffith J, Kunz WS, Pohjoismaki JLO. 2019. Replication fork rescue in mammalian mitochondria. Sci Rep. 9(1):8785.
  • Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, et al. 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 429(6990):417–423.
  • Tsurumi T, Lehman IR. 1990. Release of RNA polymerase from vero cell mitochondria after herpes simplex virus type 1 infection. J Virol. 64(1):450–452.
  • Uhler JP, Falkenberg M. 2015. Primer removal during mammalian mitochondrial DNA replication. DNA Repair. 34:28–38.
  • Uhler JP, Thorn C, Nicholls TJ, Matic S, Milenkovic D, Gustafsson CM, Falkenberg M. 2016. MGME1 processes flaps into ligatable nicks in concert with DNA polymerase gamma during mtDNA replication. Nucleic Acids Res. 44(12):5861–5871.
  • 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(3):211–212.
  • Viscomi C, Zeviani M. 2017. MtDNA-maintenance defects: syndromes and genes. J Inherit Metab Dis. 40(4):587–599.
  • 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(35):25791–25802.
  • Wanrooij S, Fuste JM, Farge G, Shi Y, Gustafsson CM, Falkenberg M. 2008. Human mitochondrial RNA polymerase primes lagging-strand DNA synthesis in vitro. Proc Natl Acad Sci USA. 105(32):11122–11127.
  • Wanrooij S, Miralles Fuste J, Stewart JB, Wanrooij PH, Samuelsson T, Larsson NG, Gustafsson CM, Falkenberg M. 2012. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13(12):1130–1137.
  • Wanrooij PH, Uhler JP, Shi Y, Westerlund F, Falkenberg M, Gustafsson CM. 2012. A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop. Nucleic Acids Res. 40(20):10334–10344.
  • Wisnovsky S, Jean SR, Kelley SO. 2016. Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes. Nat Chem Biol. 12(7):567–573.
  • Wong TW, Clayton DA. 1985. Isolation and characterization of a DNA primase from human mitochondria. J Biol Chem. 260(21):11530–11535.
  • Wong TS, Rajagopalan S, Townsley FM, Freund SM, Petrovich M, Loakes D, Fersht AR. 2009. Physical and functional interactions between human mitochondrial single-stranded DNA-binding protein and tumour suppressor p53. Nucleic Acids Res. 37(2):568–581.
  • Wu CC, Lin JLJ, Yang-Yen HF, Yuan HS. 2019. A unique exonuclease ExoG cleaves between RNA and DNA in mitochondrial DNA replication. Nucleic Acids Res. 47(10):5405–5419.
  • Xu B, Clayton DA. 1995. A persistent RNA-DNA hybrid is formed during transcription at a phylogenetically conserved mitochondrial DNA sequence. Mol Cell Biol. 15(1):580–589.
  • Yakubovskaya E, Chen Z, Carrodeguas JA, Kisker C, Bogenhagen DF. 2006. Functional human mitochondrial DNA polymerase gamma forms a heterotrimer. J Biol Chem. 281(1):374–382.
  • Yao NY, O’Donnell ME. 2016. Evolution of replication machines. Crit Rev Biochem Mol Biol. 51(3):135–149.
  • Yasukawa T, Reyes A, Cluett TJ, Yang MY, Bowmaker M, Jacobs HT, Holt IJ. 2006. Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strand. EMBO J. 25(22):5358–5371.
  • Yasukawa T, Yang MY, Jacobs HT, Holt IJ. 2005. A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol Cell. 18(6):651–662.
  • Zhang H, Barcelo JM, Lee B, Kohlhagen G, Zimonjic DB, Popescu NC, Pommier Y. 2001. Human mitochondrial topoisomerase I. Proc Natl Acad Sci USA. 98(19):10608–10613.
  • Zhang H, Zhang YW, Yasukawa T, Dalla Rosa I, Khiati S, Pommier Y. 2014. Increased negative supercoiling of mtDNA in TOP1mt knockout mice and presence of topoisomerases IIalpha and IIbeta in vertebrate mitochondria. Nucleic Acids Res. 42(11):7259–7267.