PL EN


Preferences help
enabled [disable] Abstract
Number of results
2003 | 50 | 1 | 155-167
Article title

Mutations in DNA polymerase gamma cause error prone DNA synthesis in human mitochondrial disorders

Content
Title variants
Languages of publication
EN
Abstracts
EN
This paper summarizes recent advances in understanding the links between the cell's ability to maintain integrity of its mitochondrial genome and mitochondrial genetic diseases. Human mitochondrial DNA is replicated by the two-subunit DNA polymerase γ (pol γ). We investigated the fidelity of DNA replication by pol γ with and without exonucleolytic proofreading and its p55 accessory subunit. Pol γ has high base substitution fidelity due to efficient base selection and exonucleolytic proofreading, but low frameshift fidelity when copying homopolymeric sequences longer than four nucleotides. Progressive external ophthalmoplegia (PEO) is a rare disease characterized by the accumulation of large deletions in mitochondrial DNA. Recently, several mutations in the polymerase and exonuclease domains of the human pol γ have been shown to be associated with PEO. We are analyzing the effect of these mutations on the human pol γ enzyme. In particular, three autosomal dominant mutations alter amino acids located within polymerase motif B of pol γ. These residues are highly conserved among family A DNA polymerases, which include T7 DNA polymerase and E. coli pol I. These PEO mutations have been generated in pol γ to analyze their effects on overall polymerase function as well as the effects on the fidelity of DNA synthesis. One mutation in particular, Y955C, was found in several families throughout Europe, including one Belgian family and five unrelated Italian families. The Y955C mutant pol γ retains a wild-type catalytic rate but suffers a 45-fold decrease in apparent binding affinity for the incoming dNTP. The Y955C derivative is also much less accurate than is wild-type pol γ, with error rates for certain mismatches elevated by 10- to 100-fold. The error prone DNA synthesis observed for the Y955C pol γ is consistent with the accumulation of mtDNA mutations in patients with PEO. The effects of other pol γ mutations associated with PEO are discussed.
Publisher

Year
Volume
50
Issue
1
Pages
155-167
Physical description
Dates
published
2003
received
2002-09-01
accepted
2002-09-07
Contributors
  • Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, U.S.A.
  • Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, U.S.A.
author
  • Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, U.S.A.
  • Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, U.S.A.
  • Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, U.S.A.
References
  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG. (1981) Sequence and organization of the human mitochondrial genome. Nature.; 290: 457-65.
  • Astatke M, Grindley ND, Joyce CM. (1995) Deoxynucleoside triphosphate and pyrophosphate binding sites in the catalytically competent ternary complex for the polymerase reaction catalyzed by DNA polymerase I (Klenow fragment) J Biol Chem.; 270: 1945-54.
  • Bell JB, Eckert KA, Joyce CM, Kunkel TA. (1997) Base miscoding and strand misalignment errors by mutator Klenow polymerases with amino acid substitutions at tyrosine 766 in the O helix of the fingers subdomain. J Biol Chem.; 272: 7345-51.
  • Brown WM, George MJ, Wilson AC. (1979) Rapid evolution of animal mitochondrial DNA. Proc Natl Acad Sci U S A.; 76: 1967-71.
  • Carrodeguas JA, Bogenhagen DF. (2000) Protein sequences conserved in prokaryotic aminoacyl-tRNA synthetases are important for the activity of the processivity factor of human mitochondrial DNA polymerase. Nucleic Acids Res.; 28: 1237-44.
  • Carrodeguas JA, Kobayashi R, Lim SE, Copeland WC, Bogenhagen DF. (1999) The accessory subunit of Xenopus laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases. Mol Cell Biol.; 19: 4039-46.
  • 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.
  • Carroll SS, Cowart M, Benkovic SJ. (1991) A mutant of DNA polymerase I (Klenow fragment) with reduced fidelity. Biochemistry.; 30: 804-13.
  • Chi NW, Kolodner RD. (1994a) The effect of DNA mismatches on the ATPase activity of MSH1 a protein in yeast mitochondria that recognizes DNA mismatches. J Biol Chem.; 269: 29993-7.
  • Chi NW, Kolodner RD. (1994b) Purification and characterization of MSH1 a yeast mitochondrial protein that binds to DNA mismatches. J Biol Chem.; 269: 29984-92.
  • 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: 589-91.
  • 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 U S A.; 89: 7370-4.
  • Croteau DL, Bohr VA. (1997) Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem.; 272: 25409- 12.
  • Croteau DL, ap Rhys CM, Hudson EK, Dianov GL, Hansford RG, Bohr VA. (1997) An oxidative damage-specific endonuclease from rat liver mitochondria. J Biol Chem.; 272: 27338-44.
  • Croteau DL, Stierum RH, Bohr VA. (1999) Mitochondrial DNA repair pathways. Mutat Res.; 434: 137-48.
  • Delarue M, Poch O, Tordo N, Moras D, Argos P. (1990) An attempt to unify the structure of polymerases. Protein Eng.; 3: 461-7.
  • Domena JD, Mosbaugh DW. (1985) Purification of nuclear and mitochondrial uracil-DNA glycosylase from rat liver. Identification of two distinct subcellular forms. Biochemistry.; 24: 7320-8.
  • Doublie S, Tabor S, Long AM, Richardson CC, Ellenberger T. (1998) Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution. Nature.; 391: 251-8.
  • Driggers WJ, LeDoux SP, Wilson GL. (1993) Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells. J Biol Chem.; 268: 22042-5.
  • Esposito LA, Melov S, Panov A, Cottrell BA, Wallace DC. (1999) Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci U S A.; 96: 4820-5.
  • Foury F. (1989) Cloning and sequencing of the nuclear gene MIP1 encoding the catalytic subunit of the yeast mitochondrial DNA polymerase. J Biol Chem.; 264: 20552-60.
  • Foury F, Vanderstraeten S. (1992) Yeast mitochondrial DNA mutators with deficient proofreading exonucleolytic activity. EMBO J.; 11: 2717-26.
  • Friedberg EC, Walker GC, Siede W. (1995) DNA repair and mutagenesis. ASM Press, Washington DC.
  • Fry M, Loeb LA. (1986) Animal cell DNA polymerases. CRC Press, Boca Raton FL.
  • Gray H, Wong TW. (1992) Purification and identification of subunit structure of the human mitochondrial DNA polymerase. J Biol Chem.; 267: 5835-41.
  • Graziewicz MA, Day BJ, Copeland WC. (2002) The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res.; 30: 2817-24.
  • Insdorf NF, Bogenhagen DF. (1989) DNA polymerase gamma from Xenopus laevis. I. The identification of a high molecular weight catalytic subunit by a novel DNA polymerase photolabeling procedure. J Biol Chem.; 264: 21491-7.
  • Ito J, Braithwaite DK. (1990) Yeast mitochondrial DNA polymerase is related to the family A DNA polymerases. Nucleic Acids Res.; 18: 6716.
  • Ito J, Braithwaite DK. (1991) Compilation and alignment of DNA polymerase sequences. Nucleic Acids Res.; 19: 4045-57.
  • Johnson AA, Johnson KA. (2001) Fidelity of nucleotide incorporation by human mitochondrial DNA polymerase. J Biol Chem.; 276: 38090-6.
  • Johnson AA, Tsai Y, Graves SW, Johnson KA. (2000) Human mitochondrial DNA polymerase holoenzyme: reconstitution and characterization. Biochemistry.; 39: 1702-8.
  • Kaukonen JA, Amati P, Suomalainen A, Rotig A, Piscaglia MG, Salvi F, Weissenbach J, Fratta G, Comi G, Peltonen L, Zeviani M. (1996) An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p. Am J Hum Genet.; 58: 763-9.
  • 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: 782-5.
  • Kiefer JR, Mao C, Braman JC, Beese LS. (1998) Visualizing DNA replication in a catalytically active Bacillus DNA polymerase crystalt. Nature.; 391: 304-7.
  • Kornberg A, Baker TA. (1992) DNA replication. Second edn. W.H. Freeman and Co., New York.
  • Kunkel TA, Soni A. (1988) Exonucleolytic proofreading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma. J Biol Chem.; 263: 4450-9.
  • Kunkel TA, Mosbaugh DW. (1989) Exonucleolytic proofreading by a mammalian DNA polymerase gamma. Biochemistry.; 28: 988-95
  • Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi G, Zeviani M. (2002) Mutations of mitochondrial DNA polymerase gamma are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol.; 52: 211-9.
  • LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K, Bohr VA. (1992) Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis.; 13: 1967-73.
  • LeDoux SP, Driggers WJ, Hollensworth BS, Wilson GL. (1999) Repair of alkylation and oxidative damage in mitochondrial DNA. Mutat Res.; 434: 149-59.
  • Lewis DL, Farr CL, Wang Y, Lagina ATr, Kaguni LS. (1996) Catalytic subunit of mitochondrial DNA polymerase from Drosophila embryos. Cloning bacterial overexpression and biochemical characterization. J Biol Chem.; 271: 23389-94.
  • 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: 38197-203.
  • 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 U S A.; 95: 12244-8.
  • 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: 38555-62.
  • 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 replicationent. Science.; 286: 774-9.
  • Minnick DT, Bebenek K, Osheroff WP, Turner RM Jr, Astatke M, Liu L, Kunkel TA, Joyce CM. (1999) Side chains that influence fidelity at the polymerase active site of Escherichia coli DNA polymerase I (Klenow fragment) J Biol Chem.; 274: 3067-75.
  • Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH. (1999) Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. Ann Neurol.; 45: 54-8.
  • Nishino I, Spinazzola A, Hirano M. (1999) Thymidine phosphorylase gene mutations in MNGIE a human mitochondrial disorder. Science.; 283: 689-92.
  • Ollis DL, Brick P, Hamlin R, Xuong NG, Steitz TA. (1985) Structure of large fragment of Escherichia coli DNA polymerase I complexed with dTMP. Nature.; 313: 762-6.
  • Pinz KG, Bogenhagen DF. (1998) Efficient repair of abasic sites in DNA by mitochondrial enzymes. Mol Cell Biol.; 18: 1257-65.
  • Pinz KG, Bogenhagen DF. (2000) Characterization of a catalytically slow AP lyase activity in DNA polymerase gamma and other family A DNA polymerases. J Biol Chem.; 275: 12509-14.
  • Polesky AH, Steitz TA, Grindley ND, Joyce CM. (1990) Identification of residues critical for the polymerase activity of the Klenow fragment of DNA polymerase I from Escherichia coli. J Biol Chem.; 265: 14579-91.
  • 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: 15225-8.
  • Richter C, Park JW, Ames BN. (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A.; 85: 6465-7.
  • Ropp PA, Copeland WC. (1995) Characterization of a new DNA polymerase from Schizosaccharomyces pombe: a probable homologue of the Saccharomyces cerevisiae DNA polymerase gamma. Gene.; 165: 103-7.
  • Ropp PA, Copeland WC. (1996) Cloning and characterization of the human mitochondrial DNA polymerase DNA polymerase gamma. Genomics.; 36: 449-58.
  • Rovio AT, Marchington DR, Donat S, Schuppe HC, Abel J, Fritsche E, Elliott DJ, Laippala P, Ahola AL, McNay D, Harrison RF, Hughes B, Barrett T, Bailey DM, Mehmet D, Jequier AM, Hargreave TB, Kao SH, Cummins JM, Barton DE, Cooke HJ, Wei YH, Wichmann L, Poulton J, Jacobs HT. (2001) Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet.; 29: 261-2.
  • Sawyer DE, Van Houten B. (1999) Repair of DNA damage in mitochondria. Mutat Res.; 434: 161-76.
  • Schmitt ME, Clayton DA. (1993) Conserved features of yeast and mammalian mitochondrial DNA replication. Curr Opin Genet Dev.; 3: 769-74.
  • Shadel GS, Clayton DA. (1997) Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem.; 66: 409-35.
  • Shigenaga MK, Hagen TM, Ames BN. (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A.; 91: 10771-8.
  • Sia EA, Butler CA, Dominska M, Greenwell P, Fox TD, Petes TD. (2000) Analysis of microsatellite mutations in the mitochondrial DNA of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A.; 97: 250-5.
  • Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM, Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT. (2000) In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem.; 275: 24818-28.
  • Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Santoro L, Toscano A, Fabrizi GM, Somer H, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M, Larsson C. (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: 223-31.
  • Stierum RH, Dianov GL, Bohr VA. (1999) Single-nucleotide patch base excision repair of uracil in DNA by mitochondrial protein extracts. Nucleic Acids Res.; 27: 3712-9.
  • 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: 219-25.
  • Tomkinson AE, Bonk RT, Linn S. (1988) Mitochondrial endonuclease activities specific for apurinic/apyrimidinic sites in DNA from mouse cells. J Biol Chem.; 263: 12532-7.
  • 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: 211-2.
  • Wallace DC. (1992) Diseases of the mitochondrial DNA. Annu Rev Biochem.; 61: 1175-212.
  • Wallace DC. (1994) Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci U S A.; 91: 8739-46.
  • Wang Y, Farr CL, Kaguni LS. (1997) Accessory subunit of mitochondrial DNA polymerase from Drosophila embryos. Cloning molecular analysis and association in the native enzyme. J Biol Chem.; 272: 13640-6.
  • Wernette CM, Kaguni LS. (1986) A mitochondrial DNA polymerase from embryos of Drosophila melanogaster. Purification subunit structure and partial characterization. J Biol Chem.; 261: 14764-70.
  • Wernette CM, Conway MC, Kaguni LS. (1988) Mitochondrial DNA polymerase from Drosophila melanogaster embryos: kinetics processivity and fidelity of DNA polymerization. Biochemistry.; 27: 6046-54.
  • Ye F, Carrodeguas JA, Bogenhagen DF. (1996) The gamma subfamily of DNA polymerases: cloning of a developmentally regulated cDNA encoding Xenopus laevis mitochondrial DNA polymerase gamma. Nucleic Acids Res.; 24: 1481-8.
  • Zhang D, Mott JL, Chang SW, Denniger G, Feng Z, Zassenhaus HP. (2000) Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis. Genomics.; 69: 151-61.
  • Zhang H, Barcelo JM, Lee B, Kohlhagen G, Zimonjic DB, Popescu NC, Pommier Y. (2001) Human mitochondrial topoisomeraseI. Proc Natl Acad Sci U S A.; 98: 10608-13.
Document Type
Publication order reference
Identifiers
YADDA identifier
bwmeta1.element.bwnjournal-article-abpv50i1p155kz
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.