Abstract
Mitochondrial genomes with multiple types of DNA deletions have been shown to accumulate with age in various tissues from humans, monkeys, rats, mice, and C. elegans. The deleted genomes have been classified based on characteristics of the deletion breakpoints such as the presence (or absence) of direct repeat sequences. The prevalence of direct repeats located precisely at deletion breakpoints in human mitochondrial DNA deleted genomes has led several investigators to propose slip replication or recombination as mechanisms of deletion formation. Other sequence motifs such as topoisomerase II cleavage recognition sites and secondary or tertiary structures have also been implicated in aiding deletion formation. We have characterized, from mouse skeletal muscle and brain tissues, the breakpoint regions from 36 mitochondrial genomes with deletions. Based on the large number of deletion breakpoints precisely flanked by small (2–4 nucleotides) direct repeats, we propose “replication jumping” as an important mechanism of deletion formation. In this model, the polymerase stutters during replication, possibly in an area that has been oxidatively modified. The nascent strand then anneals to a complementary downstream region and replication continues after the removal of any single-stranded “excess” DNA up to a double-stranded region, resulting in a mutant genome.
Similar content being viewed by others
References
Agarwal S and Sohal RS: DNA oxidative damage and life expectancy in houseflies. Proc. Natl. Acad. Sci. USA 91(25):12332–12335, 1994.
Attardi G: The elucidation of the human mitochondrial genome: a historical perspective. Bioessays 5(1): 34–39, 1986.
Bandy B and Davison AJ: Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging. Free Radical Biol. Med. 8(6):523–539, 1990.
Baumer A, Zhang C, Linnane AW and Nagley, P: Age-related human mtDNA deletions: A heterogeneous set of deletions arising at a single pair of directly repeated sequences. Am. J. Hum. Genet. 54(4):618–630, 1994.
Bibb MJ, Van Etten RA, Wright CT, Walberg MW and Clayton DA: Sequence and gene organization of mouse mitochondrial DNA. Cell 26(2 Pt2):167–180, 1981.
Blok RB, Thorburn DR, Thompson GN and Dahl HHM: A topoisomerase II cleavage site is associated with a novel mitochondrial DNA deletion. Hum. Genet. 95(1):75–81, 1995.
Bogenhagen D and Clayton DA: Mechanism of mitochondrial DNA replication in mouse L-cells: Introduction of superhelical turns into newly replicated molecules. J. Mol. Biol. 119(1):69–81, 1978.
Brossas JY, Barreau E, Courtois Y and Tréton J: Muttiple deletions in mitochondriat DNA are present in senescent mouse brain. Biochem. Biophys. Res. Comm. 202(2):654–659, 1994.
Castora FJ and Simpson MV: Search for a DNA gyrase in mammalian mitochondria. J. Biol. Chem. 254(22): 11193–11195, 1979.
Castora FJ, Vissering FF and Simpson MV: The effect of bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria. Biochim. Biophys. Acta 740(4):417–427, 1983.
Chung SS, Weindruch R, Schwarze SR, McKenzie DI and Aiken JM: Multiple age-associated mitochondrial DNA deletions in skeletal muscle of mice. Aging Clin. Exp. Res. 6(3):193–200, 1994.
Clayton DA: Replication of animal mitochondrial DNA. Cell 28(4):693–705, 1982.
Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF and Wallace DC: Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2(4):324–329, 1992.
Cortopassi GA and Arnheim N: Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucl. Acids Res. 18(23):6927–6933, 1990.
Cortopassi GA, Shibata D, Soong NW and Arnheim N: A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl. Acad. Sci. USA 89(16):7370–7374, 1992.
Degoul F, Nelson I, Amselem S, Romero N, Obermaier-Kusser B, Ponsot G, Marsac C and Lestienne P: Different mechanisms inferred from sequences of human mitochondrial DNA deletions in ocutar myopathies. Nucl. Acids Res. 19(3):493–496, 1991.
Devereaux J, Haeberli P and Smithies O: A comprehensive set of sequence analysis programs for the VAX. Nucl. Acids Res. 12(1 Pt1):387–395, 1984.
Dizdaroglu M: Oxidative damage to DNA in mammalian chromatin. Mutat. Res. 275(3–6):331–342, 1992.
Douc-Rasy S, Kayser A, Riou JF, and Riou G: ATP-independent type II topoisomerase from trypanosomes. Proc. Natl. Acad. Sci. USA 83(19):7152–7156, 1986.
Edris W, Burgett B, Stine OC and Filburn CR: Detection and quantitation by competitive PCR of an age-associated increase in a 4.8-kb deletion in rat mitochondrial DNA. Mutat. Res. 316(2):69–78, 1994.
Eimon PM, Chung SS, Lee CM, Weindruch R and Aiken JM: Age-associated mitochondrial DNA deletions in mouse skeletal muscle: comparison of different regions of the mitochondrial genome. Dev. Genet. 18(2):107–113, 1996.
Fleming JE, Miquel J, Cottrell SF, Yengoyan LS and Economos AC: Is cell aging caused by respiration-dependent injury to the mitochondrial genome? Gerontology 28(1):44–53, 1982.
Fraga CG, Shigenaga MK, Park JW, Degan P and Ames BN: Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine. Proc. Natl. Acad. Sci. USA 87(12):4533–4537, 1990.
Fragoso SP and Goldenberg S: Cloning and characterization of the gene encoding Trypanosoma cruzi DNA topoisomerase II. Mol. Biochem. Parasitol. 55(1–2):127–134, 1992.
Gadaleta MN, Rainaldi G, Lezza AMS, Milella F, Fracasso F and Cantatore P: Mitochondrial DNA copy number and mitochondrial DNA deletions in adult and senescent rats. Mutat. Res. 275(3–6):181–193, 1992.
Gudikote JP and Van Tuyle GC: Rearrangements in the shorter arc of rat mitochondrial DNA involving the region of the heavy and light strand promoters. Mutat. Res. 356(2): 275–286, 1996.
Harman, D: Free radical theory of aging: consequences of mitochondrial aging. Age 6(3):86–94, 1983.
Hattori K, Tanaka M, Sugiyama S, Obayashi T, Ito T, Satake T, Hanaki Y, Asai J, Nagano M and Ozawa T: Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am. Heart J. 121(6): 1735–1742, 1991.
Hayakawa M, Torri K, Sugiyama S, Tanaka M and Ozawa T: Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm. Biochem. Biophys. Res. Comm. 179(2):1023–1029, 1991.
Hayakawa M, Hattori K, Sugiyama S and Ozawa T: Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochem Biophys. Res. Comm. 189(2):979–985, 1992.
Hayakawa M, Sugiyama S, Hattori K, Takasawa M and Ozawa T: Age-associated damage in mitochondrial DNA in human hearts. Mol. Cell. Biochem. 119(1–2):95–103, 1993.
Holt IJ, Harding AE and Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms. Nucl. Acids Res. 17(12):4465–4469, 1989.
Katayama M, Tanaka M, Yamamoto H, Ohbayashi T, Nimura Y and Ozawa T: Deleted mitochondrial DNA in the skeletal muscle of aged individuals. Biochem. Int. 25(1):47–56, 1991.
Keefe DL, Niven-Fairchild T, Powell S and Buradagunta S: Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil. Steril. 64(3):577–583, 1995.
King SR, Krolewski MA, Marvo SL, Lipson PJ, Pogue-Geile KL, Chung JH and Jaskunas R: Nucleotide sequence analysis of in vivo recombinants between bateriophage λ DNA and pBR322. Mol. Gen. Genet. 186(4): 548–557, 1982.
Kitagawa T, Suganuma N, Nawa A, Kikkawa F, Tanaka M, Ozawa T and Tomoda Y: Rapid accumulation of deleted mitochondrial deoxyribonucleic acid in postmenopausal women. Biol. Reprod. 49(4):730–736, 1993.
Kuchino Y, Mori F, Kasai H, Inoue H, Iwai S, Miura K, Ohtsuka E and Nishimura S: Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature 327(6117): 77–79, 1987.
Kunkel TA and Mosbaugh DW: Exonucleolytic proofreading by a mammalian DNA polymerase g. Biochem 28(3): 988–995, 1989.
Lee CM, Chung SS, Kaczkowski JM, Weindruch R and Aiken JM: Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys. J. Gerontol. 48(6):B201–B205, 1993.
Lee CM, Eimon P, Weindruch R and Aiken JM: Direct repeat sequences are not required at the breakpoints of age-associated mitochondrial DNA deletions in rhesus monkeys. Mech. Ageing Dev. 75(1):69–79, 1994.
Lee HC, Pang CY, Hsu HS and Wei YH: Differential accumulation of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim. Biophys. Acta 1226(1):37–43, 1994.
Linnane AW, Marzuki S, Ozawa T and Tanaka M: Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet i(8639):642–645, 1989.
Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang CF and Marzuki S: Mitochondrial gene mutation: the aging process and degenerative diseases. Biochem. Int. 22(6):1067–1076, 1990.
Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC and Beal MF: Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann. Neurol. 34(4):609–616, 1993.
Melendy T and Ray DS: Novobiovin affinity purification of a mitochondrial type II topoisomerase from the typanosomatid Crithidia fasciculata. J. Biol. Chem. 264(3):1870–1876, 1989.
Melov S, Hertz GZ, Stormo GD and Johnson TE: Detection of deletions in the mitochondrial genome of Caenorhabditis elegans. Nucl. Acids Res. 22(6): 1075–1078, 1994.
Melov S, Lithgow GJ, Fischer DR, Tedesco PM and Johnson TE: Increased frequency of deletions in the mitochondrial genomes with age of Caenorhabditis elegans. Nucl. Acids Res. 23(8): 1419–1425, 1995.
Miquel J and Fleming JE: Theoretical and experimental support for an “oxygen radical-mitochondrial injury” hypothesis of cell aging in Free Radicals, Aging and Degenerative Diseases, edited by Johnson JE, Walford R, Harman D, Miquel J, New York, Liss, 1986, p.p. 51–74.
Mita S, Rizzuto R, Moraes C, Shanske S, Arnaudo E, Fabrizi GM, Koga Y, DiMauro S and Schon EA: Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucl. Acids Res. 18(3):561–567, 1990.
Naito A, Naito S and Ikeda H: Homology is not required for recombination mediated by DNA gyrase of Escherichia coil. Mol. Gen. Genet. 193(2):238–243, 1984.
Pang CY, Lee HC, Yang JH and Wei YH: Human skin mitochondrial DNA deletions associated with light exposure. Arch. Biochem. Biophys. 312(2):534–538, 1994.
Pasion SG, Hines JC, Aebersold R and Ray DS: Molecular cloning and expression of the gene encoding the kinetoplast-associated type II topoisomerase of Crithidia fasciculata. Mol. Biochem. Parasitol. 50(1): 57–68, 1992.
Richter C, Park PW and Ames BN: Normal damage to mitochondrial and nuclear DNA is extensive. Proc. Natl. Acad. Sci. USA. 85(17):6465–6467, 1988.
Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M and DiMauro S: A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science 244(4902):346–349, 1989.
Shibutani S, Takeshita M and Grollman AP: Insertions of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349(6308):431–434, 1991.
Shigenaga MK, Gimeno CJ and Ames BN: Urinary 8-hydroxy-2′-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc. Natl. Acad. Sci. USA 86(24):9697–9701, 1989.
Shlomai J, Zadok A and Frank D: A unique ATP-dependent DNA topoisomerase from trypanosomatids. Adv. Exp. Med. Biol. 179:409–422, 1984.
Shoffner JM, Lott MT, Voliavec AS, Soueidan SA, Costigan DA and Wallace DC: Spontaneous Kearns-Sayre/chronic external opthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc. Natl. Acad. Sci. USA 86(20):7952–7956, 1989.
Simonetti S, Chen X, DiMauro S and Schon EA: Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim. Biophys. Acta 1180(2):113–122, 1992.
Sohal RS and Brunk UT: Mitochondrial production of pro-oxidants and cellular senescence. Mutat. Res. 275(3–6):295–304, 1992.
Sohal RS, Agarwal S, Candas M, Forster MJ and Lal H: Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76(2–3):215–224, 1994.
Sohal RS and Weindruch R: Oxidative stress, caloric restriction, and aging. Science 273(5271): 59–63, 1996.
Soong NW, Hinton DR, Cortopassi G and Arnheim N: Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nature Genet. 2(4):318–323, 1992.
Spitzner JR, Chung IK and Muller MT: Eukaryotic topoisomerase II preferentially cleaves alternating purine-pyrimidine repeats. Nucl. Acids Res. 18(1):1–11, 1990.
Strauss PR, and Wang JC: The TOP2 gene of Trypanosoma brucei: a single-copy gene that shares extensive homology with other TOP2 genes encoding eukaryotic DNA topoisomerase II. Mol. Biochem. Parasitol. 38(1): 141–150, 1990.
Suganuma N, Kitagawa T, Nawa A and Tomoda Y: Human ovarian aging and mitochondrial DNA deletion. Horm. Res. 39(suppl. 1):16–21, 1993.
Sugiyama S, Hattori K, Hayakawa M and Ozawa T: Quantitative analysis of age-associated accumulation of mitochondrial DNA with deletion in human hearts. Biochem. Biophys. Res. Comm. 180(2):894–899, 1991.
Tanhauser SM and Laipis PJ: Multiple deletions are detectable in mitochondrial DNA of aging mice. J. Biol. Chem. 270(42):24769–24775, 1995.
Torii K, Sugiyama S, Tanaka M, Takagi K, Hanaki Y, Iida K, Matsuyama M, Hirabayashi N, Uno Y and Ozawa T: Aging-associated deletion of human diaphragmatic mitochondrial DNA. Am. J. Respir. Cell Mol. Biol. 6(5): 543–549, 1992.
Tzagoloff A and Myers AM: Genetics of mitochondrial biogenesis. Annu. Rev. Biochem. 55:249–285, 1986.
Van Tuyle GC, Gudikote JP, Hurt VR, Miller BB and Moore CA: Multiple, large deletions in rat mitochondrial DNA: evidence for a major hot spot. Mutat. Res. 349(1):95–107, 1996.
Volk MJ, Pugh TD, Kim M, Frith CH, Daynes RA, Ershler WB and Weindruch R: Dietary restriction from middle age attenuates age-associated lymphoma development and interleukin 6 dysregulation in C57BL/6 mice. Cancer Res. 54(11):3054–3061, 1994.
von Zglinicki T and Bimmler M: Intercellular water and ionic shifts during growth and ageing of rats. Mech. Ageing Dev. 38(2):179–187, 1987.
Vosberg HP: DNA topoisomerases: enzymes that control DNA conformation. Curr. Topics Microbiol. Immunol. 114:19–102, 1985.
Wagner JR, Hu CC and Ames BN: Endogenous oxidative damage of deoxycytidine in DNA. Proc. Natl. Acad. Sci. USA 89(8):3380–3384, 1992.
Wallace DC: Diseases of the mitochondrial DNA. Annu. Rev. Biochem. 61:1175–1212, 1992.
Yamamoto H, Tanaka M, Katayama M, Obayashi T, Nimura Y and Ozawa T: Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem. Biophys. Res. Comm. 182(2): 913–920, 1992.
Yen TC, Su JH, King KL and Wei YH: Ageing-associated 5 Kb deletion in human liver mitochondrial DNA. Biochem. Biophys. Res. Comm. 178(1):124–131, 1991.
Yen TC, Pang CY, Hsieh RH, Su CH, King KL and Wei YH: Age-dependent 6 Kb deletion in human liver mitochondrial DNA. Biochem. Int. 26(3):457–468, 1992.
Yoneda M, Katsumata K, Hayakawa M, Tanaka M and Ozawa T: Oxygen stress induces an apoptotic cell death associated with fragmentation of mitochondrial genome. Biochem. Biophys. Res. Comm. 209(2):723–729, 1995.
Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S and DiDonato S: An autosomal dominant disorder with multiple deletions of mtDNA starting at the D-loop region. Nature 339(6222):309–311, 1989.
Zhang C, Baumer A, Maxwell RJ, Linnane AW and Nagley P: Multiple mitochondrial DNA deletions in an elderly human individual. FEBS. 297(1, 2):34–38, 1992.
Zhang C, Baumer A, Mackay IR, Linnane AW and Nagley P: Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome. Hum. Mol. Genet. 4(4):751–754, 1995.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Chung, S.S., Eimon, P.M., Weindruch, R. et al. Analysis of age-associated mitochondrial DNA deletion breakpoint regions from mice suggests a novel model of deletion formation. AGE 19, 117–128 (1996). https://doi.org/10.1007/BF02434081
Issue Date:
DOI: https://doi.org/10.1007/BF02434081