Biopolym. Cell. 2017; 33(1):3-23.
Reviews
Aberrant DNA glycosylase-initiated repair pathway of free radicals in-duced DNA damage: implications for age-related diseases and natural aging
1Matkarimov B. T., 2Saparbaev M. K.
  1. National laboratory Astana, Nazarbayev University,
    53, Kabanbay batyr Ave., Astana, Kazakhstan, 010000
  2. CNRS UMR 8126, Universit Paris-Sud 11, Institut Gustave Roussy
    114, rue Edouard Vaillant, Villejuif, France, 94805

Abstract

Aerobic cellular respiration generates reactive oxygen species (ROS), which can damage macro-molecules including lipids, proteins and DNA. It was proposed that aging is a consequence of accumulation of naturally occurring unrepaired oxidative DNA damage. In human cells, approximately 2000 to 8000 DNA lesions occur per hour in each cell, i.e. 40000 to 200000 per cell per day. DNA repair systems are able to discriminate between regular and modified bases. For example, DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, mismatched pairs between two regular bases occur due to spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Base excision repair (BER) and mismatch repair (MMR) pathways initiated by mismatch-specific adenine- and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) can recognize and remove normal DNA bases in mismatched DNA duplexes. Under certain circumstances in DNA repair deficient cells bacterial MutY and human TDG can act in an aberrant manner: MutY and TDG remove Adenine and Thymine opposite to misincorporated 8-oxoguanine and damaged Adenine, respectively. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in an aberrant manner and introduce genome instability in the presence of unrepaired DNA lesions. Both accumulation of oxidative DNA damage in cells and the aberrant DNA repair can contribute to cancer, brain disorders and premature senescence.
Keywords: oxidative DNA damage, crystal structure, base excision repair, nucleotide incision repair, AP endonuclease

References

[1] Bjelland S, Seeberg E. Mutagenicity, toxicity and repair of DNA base damage induced by oxidation. Mutat Res. 2003;531(1-2):37-80. Review.
[2] Cadet J, Douki T, Gasparutto D, Ravanat JL. Oxidative damage to DNA: formation, measurement and biochemical features. Mutat Res. 2003;531(1-2):5-23. Review.
[3] Dizdaroglu M. Oxidatively induced DNA damage: mechanisms, repair and disease. Cancer Lett. 2012;327(1-2):26-47. Review.
[4] Teoule R, Bert C, Bonicel A. Thymine fragment damage retained in the DNA polynucleotide chain after gamma irradiation in aerated solutions. II. Radiat Res. 1977;72(2):190-200.
[5] Schuchmann MN, Steenken S, Wroblewski J, von Sonntag C. Site of OH radical attack on dihydrouracil and some of its methyl derivatives. Int J Radiat Biol Relat Stud Phys Chem Med. 1984;46(3):225-32.
[6] Ganguly T, Duker NJ. Stability of DNA thymine hydrates. Nucleic Acids Res. 1991;19(12):3319-23.
[7] Grollman AP, Moriya M. Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet. 1993;9(7):246-9.
[8] Kreutzer DA, Essigmann JM. Oxidized, deaminated cytosines are a source of C --> T transitions in vivo. Proc Natl Acad Sci U S A. 1998;95(7):3578-82.
[9] Kunkel TA, Bebenek K. DNA replication fidelity. Annu Rev Biochem. 2000;69:497-529.
[10] Kamiya H, Ueda T, Ohgi T, Matsukage A, Kasai H. Misincorporation of dAMP opposite 2-hydroxyadenine, an oxidative form of adenine. Nucleic Acids Res. 1995;23(5):761-6.
[11] von Sonntag C. Free-radical-induced DNA damage and its repair: a chemical perspective. 2006. 1 ed. Springer-Verlag Berlin Heidelberg. 523 p.
[12] Hix S, Morais Mda S, Augusto O. DNA methylation by tert-butyl hydroperoxide-iron (II). Free Radic Biol Med. 1995;19(3):293-301.
[13] Hix S, Kadiiska MB, Mason RP, Augusto O. In vivo metabolism of tert-butyl hydroperoxide to methyl radicals. EPR spin-trapping and DNA methylation studies. Chem Res Toxicol. 2000;13(10):1056-64.
[14] Kuraoka I, Bender C, Romieu A, Cadet J, Wood RD, Lindahl T. Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells. Proc Natl Acad Sci U S A. 2000;97(8):3832-7.
[15] Wang J, Clauson CL, Robbins PD, Niedernhofer LJ, Wang Y. The oxidative DNA lesions 8,5'-cyclopurines accumulate with aging in a tissue-specific manner. Aging Cell. 2012;11(4):714-6.
[16] Marnett LJ, Burcham PC. Endogenous DNA adducts: potential and paradox. Chem Res Toxicol. 1993;6(6):771-85. Review. Erratum in: Chem Res Toxicol 1994 Jul-Aug;7(4):583.
[17] Nair J, Barbin A, Guichard Y, Bartsch H. 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytine in liver DNA from humans and untreated rodents detected by immunoaffinity/32P-postlabeling. Carcinogenesis. 1995;16(3):613-7.
[18] Bartsch H, Nair J. Ultrasensitive and specific detection methods for exocylic DNA adducts: markers for lipid peroxidation and oxidative stress. Toxicology. 2000;153(1-3):105-14.
[19] Sidorenko VS, Yeo JE, Bonala RR, Johnson F, Schärer OD, Grollman AP. Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts. Nucleic Acids Res. 2012;40(6):2494-505.
[20] Kropachev K, Kolbanovskiy M, Liu Z, Cai Y, Zhang L, Schwaid AG, Kolbanovskiy A, Ding S, Amin S, Broyde S, Geacintov NE. Adenine-DNA adducts derived from the highly tumorigenic Dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not. Chem Res Toxicol. 2013;26(5):783-93.
[21] Krokan HE, Bjørås M. Base excision repair. Cold Spring Harb Perspect Biol. 2013;5(4):a012583. Review.
[22] Yasui, A. Alternative excision repair pathways. Cold Spring Harb. Perspect. Biol.,2013; 5:1–8.
[23] Cunningham RP. DNA glycosylases. Mutat Res. 1997;383(3):189-96.
[24] Dodson ML, Michaels ML, Lloyd RS. Unified catalytic mechanism for DNA glycosylases. J Biol Chem. 1994;269(52):32709-12.
[25] Demple B, Harrison L. Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem. 1994;63:915-48.
[26] Ischenko AA, Saparbaev MK. Alternative nucleotide incision repair pathway for oxidative DNA damage. Nature. 2002;415(6868):183-7.
[27] Gros L, Ishchenko AA, Ide H, Elder RH, Saparbaev MK. The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway. Nucleic Acids Res. 2004;32(1):73-81.
[28] Ishchenko AA, Deprez E, Maksimenko A, Brochon JC, Tauc P, Saparbaev MK. Uncoupling of the base excision and nucleotide incision repair pathways reveals their respective biological roles. Proc Natl Acad Sci U S A. 2006;103(8):2564-9.
[29] Lebedeva NA, Rechkunova NI, Lavrik OI. AP-site cleavage activity of tyrosyl-DNA phosphodiesterase 1. FEBS Lett. 2011;585(4):683-6.
[30] Lebedeva NA, Rechkunova NI, El-Khamisy SF, Lavrik OI. Tyrosyl-DNA phosphodiesterase 1 initiates repair of apurinic/apyrimidinic sites. Biochimie. 2012;94(8):1749-53.
[31] Lebedeva NA, Rechkunova NI, Ishchenko AA, Saparbaev M, Lavrik OI. The mechanism of human tyrosyl-DNA phosphodiesterase 1 in the cleavage of AP site and its synthetic analogs. DNA Repair (Amst). 2013;12(12):1037-42.
[32] Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK. AP endonuclease-independent DNA base excision repair in human cells. Mol Cell. 2004;15(2):209-20.
[33] Das A, Wiederhold L, Leppard JB, Kedar P, Prasad R, Wang H, Boldogh I, Karimi-Busheri F, Weinfeld M, Tomkinson AE, Wilson SH, Mitra S, Hazra TK. NEIL2-initiated, APE-independent repair of oxidized bases in DNA: Evidence for a repair complex in human cells. DNA Repair (Amst). 2006;5(12):1439-48.
[34] Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RL, Mackie H, Spoonde AY, Ackerman EJ, Coleman K, Tarone RE, Robbins JH. 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. 2000;275(29):22355-62.
[35] Johnson KA, Fink SP, Marnett LJ. Repair of propanodeoxyguanosine by nucleotide excision repair in vivo and in vitro. J Biol Chem. 1997;272(17):11434-8.
[36] Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15(7):465-81. Review.
[37] Pande P, Das RS, Sheppard C, Kow YW, Basu AK. Repair efficiency of (5'S)-8,5'-cyclo-2'-deoxyguanosine and (5'S)-8,5'-cyclo-2'-deoxyadenosine depends on the complementary base. DNA Repair (Amst). 2012;11(11):926-31.
[38] Theron T, Fousteri MI, Volker M, Harries LW, Botta E, Stefanini M, Fujimoto M, Andressoo JO, Mitchell J, Jaspers NG, McDaniel LD, Mullenders LH, Lehmann AR. Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne syndrome. Mol Cell Biol. 2005;25(18):8368-78.
[39] de Laat WL, Appeldoorn E, Sugasawa K, Weterings E, Jaspers NG, Hoeijmakers JH. DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair. Genes Dev. 1998;12(16):2598-609.
[40] Jiricny J. MutLalpha: at the cutting edge of mismatch repair. Cell. 2006;126(2):239-41.
[41] Peña-Diaz J, Bregenhorn S, Ghodgaonkar M, Follonier C, Artola-Borán M, Castor D, Lopes M, Sartori AA, Jiricny J. Noncanonical mismatch repair as a source of genomic instability in human cells. Mol Cell. 2012;47(5):669-80.
[42] Zlatanou A, Despras E, Braz-Petta T, Boubakour-Azzouz I, Pouvelle C, Stewart GS, Nakajima S, Yasui A, Ishchenko AA, Kannouche PL. The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol η in response to oxidative DNA damage in human cells. Mol Cell. 2011;43(4):649-62.
[43] Berdal KG, Johansen RF, Seeberg E. Release of normal bases from intact DNA by a native DNA repair enzyme. EMBO J. 1998;17(2):363-7.
[44] Xiao W, Samson L. In vivo evidence for endogenous DNA alkylation damage as a source of spontaneous mutation in eukaryotic cells. Proc Natl Acad Sci U S A. 1993;90(6):2117-21.
[45] Leitner-Dagan Y, Sevilya Z, Pinchev M, Kramer R, Elinger D, Roisman LC, Rennert HS, Schechtman E, Freedman L, Rennert G, Livneh Z, Paz-Elizur T. N-methylpurine DNA glycosylase and OGG1 DNA repair activities: opposite associations with lung cancer risk. J Natl Cancer Inst. 2012;104(22):1765-9.
[46] Branum ME, Reardon JT, Sancar A. DNA repair excision nuclease attacks undamaged DNA. A potential source of spontaneous mutations. J Biol Chem. 2001;276(27):25421-6.
[47] Mu D, Bessho T, Nechev LV, Chen DJ, Harris TM, Hearst JE, Sancar A. DNA interstrand cross-links induce futile repair synthesis in mammalian cell extracts. Mol Cell Biol. 2000;20(7):2446-54.
[48] Chan KK, Zhang QM, Dianov GL. Base excision repair fidelity in normal and cancer cells. Mutagenesis. 2006;21(3):173-8. Review.
[49] Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101-33. Review.
[50] Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W. Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci U S A. 2002;99(23):14937-42.
[51] Hirano S, Tominaga Y, Ichinoe A, Ushijima Y, Tsuchimoto D, Honda-Ohnishi Y, Ohtsubo T, Sakumi K, Nakabeppu Y. Mutator phenotype of MUTYH-null mouse embryonic stem cells. J Biol Chem. 2003;278(40):38121-4.
[52] Tsai-Wu JJ, Radicella JP, Lu AL. Nucleotide sequence of the Escherichia coli micA gene required for A/G-specific mismatch repair: identity of micA and mutY. J Bacteriol. 1991;173(6):1902-10.
[53] Michaels ML, Cruz C, Grollman AP, Miller JH. Evidence that MutY and MutM combine to prevent mutations by an oxidatively damaged form of guanine in DNA. Proc Natl Acad Sci U S A. 1992;89(15):7022-5.
[54] Michaels ML, Pham L, Nghiem Y, Cruz C, Miller JH. MutY, an adenine glycosylase active on G-A mispairs, has homology to endonuclease III. Nucleic Acids Res. 1990;18(13):3841-5.
[55] Fowler RG, White SJ, Koyama C, Moore SC, Dunn RL, Schaaper RM. Interactions among the Escherichia coli mutT, mutM, and mutY damage prevention pathways. DNA Repair (Amst). 2003;2(2):159-73.
[56] Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, Bisgaard ML, Orntoft TF, Aaltonen LA, Hodgson SV, Thomas HJ, Tomlinson IP. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003;348(9):791-9.
[57] Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. J Biol Chem. 2001;276(8):5547-55.
[58] Hayashi H, Tominaga Y, Hirano S, McKenna AE, Nakabeppu Y, Matsumoto Y. Replication-associated repair of adenine:8-oxoguanine mispairs by MYH. Curr Biol. 2002;12(4):335-9.
[59] Hashimoto K, Tominaga Y, Nakabeppu Y, Moriya M. Futile short-patch DNA base excision repair of adenine:8-oxoguanine mispair. Nucleic Acids Res. 2004;32(19):5928-34.
[60] Shi G, Chang DY, Cheng CC, Guan X, Venclovas C, Lu AL. Physical and functional interactions between MutY glycosylase homologue (MYH) and checkpoint proteins Rad9-Rad1-Hus1. Biochem J. 2006;400(1):53-62.
[61] Hwang BJ, Jin J, Gunther R, Madabushi A, Shi G, Wilson GM, Lu AL. Association of the Rad9-Rad1-Hus1 checkpoint clamp with MYH DNA glycosylase and DNA. DNA Repair (Amst). 2015;31:80-90.
[62] Turco E, Ventura I, Minoprio A, Russo MT, Torreri P, Degan P, Molatore S, Ranzani GN, Bignami M, Mazzei F. Understanding the role of the Q338H MUTYH variant in oxidative damage repair. Nucleic Acids Res. 2013;41(7):4093-103.
[63] Brinkmeyer MK, David SS. Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1. DNA Repair (Amst). 2015;34:39-51.
[64] Gu Y, Parker A, Wilson TM, Bai H, Chang DY, Lu AL. Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. J Biol Chem. 2002;277(13):11135-42.
[65] Repmann S, Olivera-Harris M, Jiricny J. Influence of oxidized purine processing on strand directionality of mismatch repair. J Biol Chem. 2015;290(16):9986-99.
[66] Talhaoui I, Couve S, Gros L, Ishchenko AA, Matkarimov B, Saparbaev MK. Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands. Nucleic Acids Res. 2014;42(10):6300-13.
[67] Cortázar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E, Wirz A, Schuermann D, Jacobs AL, Siegrist F, Steinacher R, Jiricny J, Bird A, Schär P. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011;470(7334):419-23.
[68] Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, Abramowitz LK, Bartolomei MS, Rambow F, Bassi MR, Bruno T, Fanciulli M, Renner C, Klein-Szanto AJ, Matsumoto Y, Kobi D, Davidson I, Alberti C, Larue L, Bellacosa A. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011;146(1):67-79.
[69] O'Brien PJ, Ellenberger T. The Escherichia coli 3-methyladenine DNA glycosylase AlkA has a remarkably versatile active site. J Biol Chem. 2004;279(26):26876-84.
[70] O'Brien PJ, Ellenberger T. Dissecting the broad substrate specificity of human 3-methyladenine-DNA glycosylase. J Biol Chem. 2004;279(11):9750-7.
[71] Shinmura K, Yamaguchi S, Saitoh T, Takeuchi-Sasaki M, Kim SR, Nohmi T, Yokota J. Adenine excisional repair function of MYH protein on the adenine:8-hydroxyguanine base pair in double-stranded DNA. Nucleic Acids Res. 2000;28(24):4912-8.
[72] Pope MA, David SS. DNA damage recognition and repair by the murine MutY homologue. DNA Repair (Amst). 2005;4(1):91-102.
[73] Ushijima Y, Tominaga Y, Miura T, Tsuchimoto D, Sakumi K, Nakabeppu Y. A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA. Nucleic Acids Res. 2005;33(2):672-82.
[74] Bielas JH, Heddle JA. Quiescent murine cells lack global genomic repair but are proficient in transcription-coupled repair. DNA Repair (Amst). 2004;3(7):711-7.
[75] Fortini P, Dogliotti E. Mechanisms of dealing with DNA damage in terminally differentiated cells. Mutat Res. 2010;685(1-2):38-44.
[76] Nouspikel T. DNA repair in differentiated cells: some new answers to old questions. Neuroscience. 2007;145(4):1213-21.
[77] Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, Morrison CG, Passegué E. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7(2):174-85.
[78] Rossi DJ, Seita J, Czechowicz A, Bhattacharya D, Bryder D, Weissman IL. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle. 2007;6(19):2371-6.
[79] Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014;15(1):37-50.
[80] Chen Y, Li D, Wang D, Liu X, Yin N, Song Y, Lu SH, Ju Z, Zhan Q. Quiescence and attenuated DNA damage response promote survival of esophageal cancer stem cells. J Cell Biochem. 2012;113(12):3643-52.
[81] Garinis GA, Uittenboogaard LM, Stachelscheid H, Fousteri M, van Ijcken W, Breit TM, van Steeg H, Mullenders LH, van der Horst GT, Brüning JC, Niessen CM, Hoeijmakers JH, Schumacher B. Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity. Nat Cell Biol. 2009;11(5):604-15.
[82] Nassour J, Martien S, Martin N, Deruy E, Tomellini E, Malaquin N, Bouali F, Sabatier L, Wernert N, Pinte S, Gilson E, Pourtier A, Pluquet O, Abbadie C. Defective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells. Nat Commun. 2016;7:10399.
[83] Fumagalli M, Rossiello F, Mondello C, d'Adda di Fagagna F. Stable cellular senescence is associated with persistent DDR activation. PLoS One. 2014;9(10):e110969.
[84] Mallette FA, Ferbeyre G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle. 2007;6(15):1831-6.
[85] Suzuki M, Suzuki K, Kodama S, Yamashita S, Watanabe M. Persistent amplification of DNA damage signal involved in replicative senescence of normal human diploid fibroblasts. Oxid Med Cell Longev. 2012;2012:310534.
[86] Yahata T, Takanashi T, Muguruma Y, Ibrahim AA, Matsuzawa H, Uno T, Sheng Y, Onizuka M, Ito M, Kato S, Ando K. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood. 2011;118(11):2941-50.
[87] Sykora P, Wilson DM 3rd, Bohr VA. Base excision repair in the mammalian brain: implication for age related neurodegeneration. Mech Ageing Dev. 2013;134(10):440-8.
[88] Gaubatz JW, Tan BH. Aging affects the levels of DNA damage in postmitotic cells. Ann N Y Acad Sci. 1994;719:97-107.
[89] Tan BH, Bencsath FA, Gaubatz JW. Steady-state levels of 7-methylguanine increase in nuclear DNA of postmitotic mouse tissues during aging. Mutat Res. 1990;237(5-6):229-38.
[90] Hinz JM, Rodriguez Y, Smerdon MJ. Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme. Proc Natl Acad Sci U S A. 2010;107(10):4646-51.
[91] Odell ID, Barbour JE, Murphy DL, Della-Maria JA, Sweasy JB, Tomkinson AE, Wallace SS, Pederson DS. Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair. Mol Cell Biol. 2011;31(22):4623-32.
[92] Prakash S, Johnson RE, Prakash L. Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem. 2005;74:317-53.
[93] Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.
[94] Macip S, Igarashi M, Fang L, Chen A, Pan ZQ, Lee SW, Aaronson SA. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 2002;21(9):2180-8.
[95] Hubackova S, Krejcikova K, Bartek J, Hodny Z. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging (Albany NY). 2012;4(12):932-51.
[96] Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A. 1995;92(10):4337-41.
[97] Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem. 2009;284(14):9529-39.
[98] Kretova M, Sabova L, Hodny Z, Bartek J, Kollarovic G, Nelson BD, Hubackova S, Luciakova K. TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence. Cell Signal. 2014;26(12):2903-11.
[99] Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M, Shelbourne PF. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet. 2003;12(24):3359-67.
[100] Sheng Z, Oka S, Tsuchimoto D, Abolhassani N, Nomaru H, Sakumi K, Yamada H, Nakabeppu Y. 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair. J Clin Invest. 2012;122(12):4344-61.
[101] Vrouwe MG, Pines A, Overmeer RM, Hanada K, Mullenders LH. UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways. J Cell Sci. 2011;124(Pt 3):435-46.
[102] Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y. Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. EMBO J. 2008;27(2):421-32.
[103] Maga G, Villani G, Crespan E, Wimmer U, Ferrari E, Bertocci B, Hübscher U. 8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins. Nature. 2007;447(7144):606-8.
[104] Maga G, Crespan E, Wimmer U, van Loon B, Amoroso A, Mondello C, Belgiovine C, Ferrari E, Locatelli G, Villani G, Hübscher U. Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair. Proc Natl Acad Sci U S A. 2008;105(52):20689-94.
[105] Nakabeppu Y. Cellular levels of 8-oxoguanine in either DNA or the nucleotide pool play pivotal roles in carcinogenesis and survival of cancer cells. Int J Mol Sci. 2014;15(7):12543-57.
[106] Oka S, Leon J, Tsuchimoto D, Sakumi K, Nakabeppu Y. MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death. Oncogenesis. 2014;3:e121.
[107] Nakatake S, Murakami Y, Ikeda Y, Morioka N, Tachibana T, Fujiwara K, Yoshida N, Notomi S, Hisatomi T, Yoshida S, Ishibashi T, Nakabeppu Y, Sonoda KH. MUTYH promotes oxidative microglial activation and inherited retinal degeneration. JCI Insight. 2016;1(15):e87781.
[108] Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Ørntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7.
[109] Toledo LI, Murga M, Gutierrez-Martinez P, Soria R, Fernandez-Capetillo O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 2008;22(3):297-302.
[110] Cheung CT, Singh R, Kalra RS, Kaul SC, Wadhwa R. Collaborator of ARF (CARF) regulates proliferative fate of human cells by dose-dependent regulation of DNA damage signaling. J Biol Chem. 2014;289(26):18258-69.
[111] d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194-8.
[112] Minieri V, Saviozzi S, Gambarotta G, Lo Iacono M, Accomasso L, Cibrario Rocchietti E, Gallina C, Turinetto V, Giachino C. Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells. J Cell Mol Med. 2015;19(4):734-43.
[113] Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019-31.
[114] Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973-9.
[115] Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Saffrey MJ, Cameron K, von Zglinicki T. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell. 2012;11(6):996-1004.
[116] Simpson JE, Ince PG, Matthews FE, Shaw PJ, Heath PR, Brayne C, Garwood C, Higginbottom A, Wharton SB; MRC Cognitive Function and Ageing Neuropathology Study Group.. A neuronal DNA damage response is detected at the earliest stages of Alzheimer's neuropathology and correlates with cognitive impairment in the Medical Research Council's Cognitive Function and Ageing Study ageing brain cohort. Neuropathol Appl Neurobiol. 2015;41(4):483-96.
[117] Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O'Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264-78.
[118] Saini N, Roberts SA, Klimczak LJ, Chan K, Grimm SA, Dai S, Fargo DC, Boyer JC, Kaufmann WK, Taylor JA, Lee E, Cortes-Ciriano I, Park PJ, Schurman SH, Malc EP, Mieczkowski PA, Gordenin DA. The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts. PLoS Genet. 2016;12(10):e1006385.