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The accumulation of DNA repair defects is the molecular origin of carcinogenesis

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Tumor Biology

Abstract

Genomic instability has been considered to be one of the prominent factors for carcinogenesis and the development of a number of degenerative disorders, predominantly related to the aging. The cellular machineries involved in the maintenance of genomic integrity such as DNA repair and DNA damage responses are extensively characterized by a large number of studies. The failure of proper actions of such cellular machineries may lead to the devastating effects mostly inducing cancer or premature aging, even with no acute exogenous DNA damage stimuli. In this review, we especially focus on the pathophysiological aspects of the defective DNA damage responses in carcinogenesis and premature aging. Clear understanding the causes of carcinogenesis and age-related degenerative diseases will provide novel and efficient approaches for prevention and rational treatment of cancer and premature aging.

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References

  1. Nakamura J et al. Highly sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced depurination under physiological conditions. Cancer Res. 1998;58(2):222–5.

    PubMed  CAS  Google Scholar 

  2. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  PubMed  CAS  Google Scholar 

  4. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11(3):220–8.

    Article  PubMed  CAS  Google Scholar 

  5. Gorgoulis VG et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434(7035):907–13.

    Article  PubMed  CAS  Google Scholar 

  6. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408(6811):433–9.

    Article  PubMed  CAS  Google Scholar 

  7. MacDougall CA et al. The structural determinants of checkpoint activation. Genes Dev. 2007;21(8):898–903.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Byun TS et al. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19(9):1040–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Sartori AA et al. Human CtIP promotes DNA end resection. Nature. 2007;450(7169):509–14.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Shiotani B, Zou L. Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell. 2009;33(5):547–58.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Willis J et al. APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci U S A. 2013;110(26):10592–7.

    Article  PubMed  CAS  Google Scholar 

  12. Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300(5625):1542–8.

    Article  PubMed  CAS  Google Scholar 

  13. Kumagai A et al. TopBP1 activates the ATR-ATRIP complex. Cell. 2006;124(5):943–55.

    Article  PubMed  CAS  Google Scholar 

  14. Lee J, Kumagai A, Dunphy WG. The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem. 2007;282(38):28036–44.

    Article  PubMed  CAS  Google Scholar 

  15. Bartek J, Mailand N. TOPping up ATR activity. Cell. 2006;124(5):888–90.

    Article  PubMed  CAS  Google Scholar 

  16. Garcia V, Furuya K, Carr AM. Identification and functional analysis of TopBP1 and its homologs. DNA Repair (Amst). 2005;4(11):1227–39.

    Article  CAS  Google Scholar 

  17. Yan S, Michael WM. TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks. J Cell Biol. 2009;184(6):793–804.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Gong Z et al. BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell. 2010;37(3):438–46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Wang J, Gong Z, Chen J. MDC1 collaborates with TopBP1 in DNA replication checkpoint control. J Cell Biol. 2011;193(2):267–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Duursma AM et al. A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol Cell. 2013;50(1):116–22.

    Article  PubMed  CAS  Google Scholar 

  21. Liu S et al. Claspin operates downstream of TopBP1 to direct ATR signaling towards Chk1 activation. Mol Cell Biol. 2006;26(16):6056–64.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Sanchez Y et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997;277(5331):1497–501.

    Article  PubMed  CAS  Google Scholar 

  23. Jin J et al. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 2003;17(24):3062–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Thanasoula M et al. ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres. EMBO J. 2012;31(16):3398–410.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Peng A et al. Repo-man controls a protein phosphatase 1-dependent threshold for DNA damage checkpoint activation. Curr Biol. 2010;20(5):387–96.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Lowe J et al. Regulation of the Wip1 phosphatase and its effects on the stress response. Front Biosci. 2012;17:1480–98.

    Article  CAS  Google Scholar 

  27. Yoo HY et al. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell. 2004;117(5):575–88.

    Article  PubMed  CAS  Google Scholar 

  28. Mamely I et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol. 2006;16(19):1950–5.

    Article  PubMed  CAS  Google Scholar 

  29. Pandita TK, Dhar S. Influence of ATM function on interactions between telomeres and nuclear matrix. Radiat Res. 2000;154(2):133–9.

    Article  PubMed  CAS  Google Scholar 

  30. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155–68.

    Article  PubMed  CAS  Google Scholar 

  31. Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001;15(17):2177–96.

    Article  PubMed  CAS  Google Scholar 

  32. Fernandez-Capetillo O, Celeste A, Nussenzweig A. Focusing on foci: H2AX and the recruitment of DNA-damage response factors. Cell Cycle. 2003;2(5):426–7.

    Article  PubMed  CAS  Google Scholar 

  33. Mah LJ, El-Osta A, Karagiannis TC. gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia. 2010;24(4):679–86.

    Article  PubMed  CAS  Google Scholar 

  34. Stucki M et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell. 2005;123(7):1213–26.

    Article  PubMed  CAS  Google Scholar 

  35. Lee JH, Paull TT. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science. 2004;304(5667):93–6.

    Article  PubMed  CAS  Google Scholar 

  36. Uziel T et al. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 2003;22(20):5612–21.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Berkovich E, Monnat Jr RJ, Kastan MB. Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat Cell Biol. 2007;9(6):683–90.

    Article  PubMed  CAS  Google Scholar 

  38. Lim DS et al. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature. 2000;404(6778):613–7.

    Article  PubMed  CAS  Google Scholar 

  39. Matsuoka S et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316(5828):1160–6.

    Article  PubMed  CAS  Google Scholar 

  40. Falck J et al. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 2001;410(6830):842–7.

    Article  PubMed  CAS  Google Scholar 

  41. Smith J et al. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112.

    Article  PubMed  CAS  Google Scholar 

  42. Ljungman M. Activation of DNA damage signaling. Mutat Res. 2005;577(1–2):203–16.

    Article  PubMed  CAS  Google Scholar 

  43. Cha H et al. Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response. Cancer Res. 2010;70(10):4112–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Celeste A et al. Genomic instability in mice lacking histone H2AX. Science. 2002;296(5569):922–7.

    Article  PubMed  CAS  Google Scholar 

  45. Celeste A et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol. 2003;5(7):675–9.

    Article  PubMed  CAS  Google Scholar 

  46. Lowe JM et al. Nuclear factor-kappaB (NF-kappaB) is a novel positive transcriptional regulator of the oncogenic Wip1 phosphatase. J Biol Chem. 2010;285(8):5249–57.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14(4):197–210.

    Article  CAS  Google Scholar 

  48. Guo Z et al. ATM activation by oxidative stress. Science. 2010;330(6003):517–21.

    Article  PubMed  CAS  Google Scholar 

  49. Yang C et al. Aurora-B mediated ATM serine 1403 phosphorylation is required for mitotic ATM activation and the spindle checkpoint. Mol Cell. 2011;44(4):597–608.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Rothkamm K et al. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol. 2003;23(16):5706–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Hartlerode AJ, Scully R. Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J. 2009;423(2):157–68.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Rupnik A, Lowndes NF, Grenon M. MRN and the race to the break. Chromosoma. 2010;119(2):115–35.

    Article  PubMed  Google Scholar 

  53. Sancar A et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 2004;73:39–85.

    Article  PubMed  CAS  Google Scholar 

  54. Botuyan MV et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006;127(7):1361–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Huyen Y et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature. 2004;432(7015):406–11.

    Article  PubMed  CAS  Google Scholar 

  56. Stewart GS et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009;136(3):420–34.

    Article  PubMed  CAS  Google Scholar 

  57. Doil C et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009;136(3):435–46.

    Article  PubMed  CAS  Google Scholar 

  58. Kusch T et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science. 2004;306(5704):2084–7.

    Article  PubMed  CAS  Google Scholar 

  59. Ikura T et al. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol Cell Biol. 2007;27(20):7028–40.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Nagai S et al. Functional targeting of DNA damage to a nuclear pore-associated SUMO-dependent ubiquitin ligase. Science. 2008;322(5901):597–602.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Giunta S, Belotserkovskaya R, Jackson SP. DNA damage signaling in response to double-strand breaks during mitosis. J Cell Biol. 2010;190(2):197–207.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Symington LS, Gautier J. Double-strand break end resection and repair pathway choice. Annu Rev Genet. 2011;45:247–71.

    Article  PubMed  CAS  Google Scholar 

  63. Franco M et al. Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood. 2011;118(10):2906–17.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Gottlieb TM, Jackson SP. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 1993;72(1):131–42.

    Article  PubMed  CAS  Google Scholar 

  65. Yang J et al. ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis. 2003;24(10):1571–80.

    Article  PubMed  CAS  Google Scholar 

  66. Meek K, Dang V, Lees-Miller SP. DNA-PK: the means to justify the ends? Adv Immunol. 2008;99:33–58.

    Article  PubMed  CAS  Google Scholar 

  67. Hill R, Lee PW. The DNA-dependent protein kinase (DNA-PK): more than just a case of making ends meet? Cell Cycle. 2010;9(17):3460–9.

    Article  PubMed  CAS  Google Scholar 

  68. McVey M, Lee SE. MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 2008;24(11):529–38.

    Article  PubMed  CAS  Google Scholar 

  69. Truong LN et al. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci U S A. 2013;110(19):7720–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008;9(8):619–31.

    PubMed  CAS  Google Scholar 

  71. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–46.

    Article  PubMed  CAS  Google Scholar 

  72. Bignami M, Casorelli I, Karran P. Mismatch repair and response to DNA-damaging antitumour therapies. Eur J Cancer. 2003;39(15):2142–9.

    Article  PubMed  CAS  Google Scholar 

  73. Fortini P et al. The type of DNA glycosylase determines the base excision repair pathway in mammalian cells. J Biol Chem. 1999;274(21):15230–6.

    Article  PubMed  CAS  Google Scholar 

  74. de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis. 2000;21(3):453–60.

    Article  PubMed  Google Scholar 

  75. Fisher AE et al. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol Cell Biol. 2007;27(15):5597–605.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Jilani A et al. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3′-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J Biol Chem. 1999;274(34):24176–86.

    Article  PubMed  CAS  Google Scholar 

  77. Izumi T et al. Requirement for human AP endonuclease 1 for repair of 3′-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Carcinogenesis. 2000;21(7):1329–34.

    Article  PubMed  CAS  Google Scholar 

  78. Sobol RW et al. The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature. 2000;405(6788):807–10.

    Article  PubMed  CAS  Google Scholar 

  79. Caldecott KW. Mammalian single-strand break repair: mechanisms and links with chromatin. DNA Repair (Amst). 2007;6(4):443–53.

    Article  CAS  Google Scholar 

  80. Whitehouse CJ et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell. 2001;104(1):107–17.

    Article  PubMed  CAS  Google Scholar 

  81. Parsons JL et al. Poly(ADP-ribose) polymerase-1 protects excessive DNA strand breaks from deterioration during repair in human cell extracts. FEBS J. 2005;272(8):2012–21.

    Article  PubMed  CAS  Google Scholar 

  82. Girard PM et al. Radiosensitivity in Nijmegen breakage syndrome cells is attributable to a repair defect and not cell cycle checkpoint defects. Cancer Res. 2000;60(17):4881–8.

    PubMed  CAS  Google Scholar 

  83. Banin S et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 1998;281(5383):1674–7.

    Article  PubMed  CAS  Google Scholar 

  84. Canman CE et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science. 1998;281(5383):1677–9.

    Article  PubMed  CAS  Google Scholar 

  85. Lakin ND, Jackson SP. Regulation of p53 in response to DNA damage. Oncogene. 1999;18(53):7644–55.

    Article  PubMed  CAS  Google Scholar 

  86. Reinhardt HC, Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 2012;28(3):128–36.

    Article  PubMed  CAS  Google Scholar 

  87. Wang X, D'Andrea AD. The interplay of Fanconi anemia proteins in the DNA damage response. DNA Repair (Amst). 2004;3(8–9):1063–9.

    Article  CAS  Google Scholar 

  88. Kim H, D'Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 2012;26(13):1393–408.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. O'Driscoll M et al. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33(4):497–501.

    Article  PubMed  CAS  Google Scholar 

  90. Abbott DW et al. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem. 1999;274(26):18808–12.

    Article  PubMed  CAS  Google Scholar 

  91. Kaneko H, Kondo N. Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. Expert Rev Mol Diagn. 2004;4(3):393–401.

    Article  PubMed  CAS  Google Scholar 

  92. Varley JM. Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat. 2003;21(3):313–20.

    Article  PubMed  CAS  Google Scholar 

  93. Kaneko H, Fukao T, Kondo N. The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining. Adv Biophys. 2004;38:45–64.

    Article  CAS  Google Scholar 

  94. Henriksson G et al. Enhanced DNA-dependent protein kinase activity in Sjogren's syndrome B cells. Rheumatology (Oxford). 2004;43(9):1109–15.

    Article  CAS  Google Scholar 

  95. Xie L et al. Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner. Proc Natl Acad Sci U S A. 2011;108(24):9939–44.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Sodir NM et al. Endogenous Myc maintains the tumor microenvironment. Genes Dev. 2011;25(9):907–16.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Zhou BB et al. Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity. J Biol Chem. 2000;275(14):10342–8.

    Article  PubMed  CAS  Google Scholar 

  98. Tuveson D, Hanahan D. Translational medicine: cancer lessons from mice to humans. Nature. 2011;471(7338):316–7.

    Article  PubMed  CAS  Google Scholar 

  99. Sharma RA, Dianov GL. Targeting base excision repair to improve cancer therapies. Mol Aspects Med. 2007;28(3–4):345–74.

    Article  PubMed  CAS  Google Scholar 

  100. Dianov GL, Parsons JL. Co-ordination of DNA single strand break repair. DNA Repair (Amst). 2007;6(4):454–60.

    Article  CAS  Google Scholar 

  101. El-Khamisy SF, Caldecott KW. DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1. Neuroscience. 2007;145(4):1260–6.

    Article  PubMed  CAS  Google Scholar 

  102. Wang R et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008;14(4):312–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  103. El-Khamisy SF, Caldecott KW. TDP1-dependent DNA single-strand break repair and neurodegeneration. Mutagenesis. 2006;21(4):219–24.

    Article  PubMed  CAS  Google Scholar 

  104. Nie Z et al. Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1). Bioorg Med Chem Lett. 2013;23(12):3662–6.

    Article  PubMed  CAS  Google Scholar 

  105. Hikichi Y et al. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012;11(3):700–9.

    Article  PubMed  CAS  Google Scholar 

  106. Donmez G. The neurobiology of sirtuins and their role in neurodegeneration. Trends Pharmacol Sci. 2012;33(9):494–501.

    Article  PubMed  CAS  Google Scholar 

  107. Fukao T et al. Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype. Oncogene. 2004;23(8):1498–506.

    Article  PubMed  CAS  Google Scholar 

  108. O'Driscoll M, Jeggo PA. Clinical impact of ATR checkpoint signalling failure in humans. Cell Cycle. 2003;2(3):194–5.

    PubMed  Google Scholar 

  109. Lukas C et al. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO J. 2004;23(13):2674–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  110. Montes de Oca R et al. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood. 2005;105(3):1003–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We greatly thank Dr. Jean Dahl (retired, Harvard Medical School, MA, USA) and Dr. Nurten Saydam (Medical University of Vienna, Vienna, Austria) for critical reading and discussion and all the researchers who have made great contributions to this research field. This work was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012011382, 2012044458—H Yim and 20110031698—HJ Cha).

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Cha, HJ., Yim, H. The accumulation of DNA repair defects is the molecular origin of carcinogenesis. Tumor Biol. 34, 3293–3302 (2013). https://doi.org/10.1007/s13277-013-1038-y

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