Review Article | Published:

The DNA-damage response in human biology and disease

Nature volume 461, pages 10711078 (22 October 2009) | Download Citation

Abstract

The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Repair of endogenous DNA damage. Cold Spring Harb. Symp. Quant. Biol. 65, 127–134 (2000)An excellent overview of the extent of endogenous DNA damage, the types of DNA lesions arising from cell autonomous sources, and the pathways that repair such lesions.

  2. 2.

    , , , & Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 160, 1–40 (2006)

  3. 3.

    , , & Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol. Chem. 387, 365–372 (2006)

  4. 4.

    & DNA double-strand breaks: signalling, repair and the cancer connection. Nature Genet. 27, 247–254 (2001)

  5. 5.

    DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog. Nucleic Acid Res. Mol. Biol. 35, 95–125 (1988)

  6. 6.

    & The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191–1308 (1981)Classical overview of epidemiological evidence for DNA-damaging environmental insults implicated as carcinogens, and suggestions for measures to prevent such tumours.

  7. 7.

    , , , & Environmental and chemical carcinogenesis. Semin. Cancer Biol. 14, 473–486 (2004)

  8. 8.

    , , & Classification of anticancer drugs—a new system based on therapeutic targets. Cancer Treat. Rev. 29, 515–523 (2003)

  9. 9.

    , & Psoriasis treatment: traditional therapy. Ann. Rheum. Dis. 64 (suppl. 2). 83–86 (2005)

  10. 10.

    & The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007)

  11. 11.

    & Interfaces between the detection, signalling, and repair of DNA damage. Science 297, 547–551 (2002)

  12. 12.

    & Surviving the Breakup: The DNA damage checkpoint. Annu. Rev. Genet. 40, 209–235 (2006)

  13. 13.

    The multifaceted mismatch-repair system. Nature Rev. Mol. Cell Biol. 7, 335–346 (2006)

  14. 14.

    , & Base-excision repair of oxidative DNA damage. Nature 447, 941–950 (2007)

  15. 15.

    Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001)A highly informative review of the links between DNA damage, DNA-repair pathways and their defects contributing to tumorigenesis.

  16. 16.

    et al. DNA Repair and Mutagenesis 2nd edn (ASM Press, 2006)An excellent, comprehensive multi-author book covering essentially the entire field of DNA repair, from basic mechanisms in diverse organisms, to human diseases associated with defective DNA repair.

  17. 17.

    & DNA polymerases and human disease. Nature Rev. Genet. 9, 594–604 (2008)

  18. 18.

    The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 283, 1–5 (2008)

  19. 19.

    , & Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008)

  20. 20.

    & MMEJ repair of double-strand breaks (director’s cut): deleted sequences and alternative endings. Trends Genet. 24, 529–538 (2008)

  21. 21.

    & The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes Dev. 19, 2925–2940 (2005)

  22. 22.

    & ATR: an essential regulator of genome integrity. Nature Rev. Mol. Cell Biol. 9, 616–627 (2008)

  23. 23.

    & DNA damage checkpoints: from initiation to recovery or adaptation. Curr. Opin. Cell Biol. 19, 238–245 (2007)

  24. 24.

    ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003)Describes the key DDR kinases ATM, ATR and DNA-PK, provides an overview of their substrates, and outlines the cellular pathways affected by DNA-damage signalling.

  25. 25.

    , , & Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008)

  26. 26.

    & Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004)

  27. 27.

    & The DNA damage response pathways: at the crossroad of protein modifications. Cell Res. 18, 8–16 (2008)

  28. 28.

    et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007)Milestone report on the proteomic identification of ATM/ATR substrates and their assignment to various cellular functions, including RNA processing and other protein networks not previously recognized as DDR targets.

  29. 29.

    & Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729–740 (2007)

  30. 30.

    , & An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008)

  31. 31.

    & The emerging role of nuclear architecture in DNA repair and genome maintenance. Nature Rev. Mol. Cell Biol. 10, 243–254 (2009)

  32. 32.

    et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nature Cell Biol. 8, 870–876 (2006)

  33. 33.

    et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457, 57–62 (2009)

  34. 34.

    et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591–596 (2009)

  35. 35.

    & The cellular response to general and programmed DNA double-strand breaks. DNA Repair 3, 781–796 (2004)

  36. 36.

    , & Leukemia and lymphoma: a cost of doing business for adaptive immunity. Genes Dev. 20, 1539–1544 (2006)

  37. 37.

    , & The role of the DNA double-strand break response network in meiosis. DNA Repair 3, 1149–1164 (2004)

  38. 38.

    & Replication and protection of telomeres. Nature 447, 924–931 (2007)

  39. 39.

    Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005)

  40. 40.

    , & Functional links between telomeres and proteins of the DNA-damage response. Genes Dev. 18, 1781–1799 (2004)References 39 and 40 illustrate the intimate links between the telomere maintenance and DDR machineries.

  41. 41.

    DNA damage response at functional and dysfunctional telomeres. Genes Dev. 22, 125–140 (2008)

  42. 42.

    et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biol. 6, 168–170 (2004)

  43. 43.

    et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006)Reports a powerful mouse model of multifaceted premature ageing, based on engineered deficiency in the Xpf gene involved in transcription-coupled NER.

  44. 44.

    & Cellular senescence and organismal aging. Mech. Ageing Dev. 129, 467–474 (2008)

  45. 45.

    , & Transcription domain-associated repair in human cells. Mol. Cell. Biol. 26, 8722–8730 (2006)

  46. 46.

    , , & Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc. Natl Acad. Sci. USA 103, 10017–10022 (2006)

  47. 47.

    & DNA repair defects in stem cell function and aging. Annu. Rev. Med. 56, 495–508 (2005)

  48. 48.

    et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007)

  49. 49.

    et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007)

  50. 50.

    & Emerging links between the biological clock and the DNA damage response. Chromosoma 116, 331–339 (2007)

  51. 51.

    et al. HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability. Nature Cell Biol. 9, 391–401 (2007)

  52. 52.

    , , & Circadian oscillation of nucleotide excision repair in mammalian brain. Proc. Natl Acad. Sci. USA 106, 2864–2867 (2009)

  53. 53.

    Update on avian influenza A (H5N1) virus infection in humans. N. Engl. J. Med. 358, 261–273 (2008)

  54. 54.

    & A role for RAD51 and homologous recombination in Trypanosoma brucei antigenic variation. Genes Dev. 13, 2875–2888 (1999)

  55. 55.

    , & Using or abusing: viruses and the cellular DNA damage response. Trends Microbiol. 15, 119–126 (2007)

  56. 56.

    & Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 98, 1505–1511 (2007)

  57. 57.

    & Knock-down of DNA ligase IV/ XRCC4 by RNAi inhibits herpes simplex virus type I DNA replication. J. Biol. Chem. 282, 10865–10872 (2007)

  58. 58.

    et al. Chk2 is required for HSV-1 ICP0-mediated G2/M arrest and enhancement of virus growth. Virology 375, 13–23 (2008)

  59. 59.

    & Following the path of the virus: the exploitation of host DNA repair mechanisms by retroviruses. ACS Chem. Biol. 1, 217–226 (2006)

  60. 60.

    , & The cancer genome. Nature 458, 719–724 (2009)A comprehensive overview of cancer-predisposing mutations and advances in cancer genetics.

  61. 61.

    , & Genetic instabilities in human cancers. Nature 396, 643–649 (1998)

  62. 62.

    & Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002)

  63. 63.

    & Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nature Rev. Cancer 8, 180–192 (2008)

  64. 64.

    et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005)

  65. 65.

    et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005)References 64 and 65 provide evidence for activation of the DDR machinery in early human oncogenic lesions and models of oncogenic transformation, and propose that the DNA-damage checkpoint activated by oncogene-evoked replication stress and DNA breakage provides an inducible barrier against tumour progression.

  66. 66.

    , & Defective DNA repair and neurodegenerative disease. Cell 130, 991–1004 (2007)

  67. 67.

    & The involvement of DNA-damage and -repair defects in neurological dysfunction. Am. J. Hum. Genet. 82, 539–566 (2008)

  68. 68.

    , , & DNA repair, mitochondria, and neurodegeneration. Neuroscience 145, 1318–1329 (2007)

  69. 69.

    Single-strand break repair and genetic disease. Nature Rev. Genet. 9, 619–631 (2008)

  70. 70.

    & Transcription—guarding the genome by sensing DNA damage. Nature Rev. Cancer 4, 727–737 (2004)

  71. 71.

    Expandable DNA repeats and human disease. Nature 447, 932–940 (2007)

  72. 72.

    & Features of trinucleotide repeat instability in vivo. Cell Res. 18, 198–213 (2008)

  73. 73.

    , , & Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair 7, 1110–1120 (2008)

  74. 74.

    & The biology of infertility: research advances and clinical challenges. Nature Med. 14, 1197–1213 (2008)

  75. 75.

    , , , & DNA damage response in human testes and testicular germ cell tumours: biology and implications for therapy. Int. J. Androl. 30, 282–291 (2007)

  76. 76.

    , & Age to survive: DNA damage and aging. Trends Genet. 24, 77–85 (2008)A thought-provoking review of the evidence for causative links between DNA-damage accumulation and organismal ageing, which proposes the concept of a survival response that allows the organism’s resources to be shifted from emphasis on growth, to survival of DNA damage and other stresses.

  77. 77.

    , , , & Cellular senescence in aging primates. Science 311, 1257 (2006)

  78. 78.

    & How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007)

  79. 79.

    et al. Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Mol. Ther. 14, 525–535 (2006)

  80. 80.

    , & Repopulating defect of mismatch repair-deficient hematopoietic stem cells. Blood 102, 1626–1633 (2003)

  81. 81.

    & p53 down-regulation: a new molecular mechanism involved in ischaemic preconditioning. FEBS Lett. 555, 302–306 (2003)

  82. 82.

    & p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007)

  83. 83.

    , & DNA damage, p53, apoptosis and vascular disease. Mutat. Res. 621, 75–86 (2007)

  84. 84.

    et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 4, 377–389 (2006)

  85. 85.

    DNA damage responses: mechanisms and roles in human disease. 2007 G.H.A. Clowes Memorial Award Lecture. Mol. Cancer Res. 6, 517–524 (2008)

  86. 86.

    et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006)

  87. 87.

    , , , & DNA repair pathways as targets for cancer therapy. Nature Rev. Cancer 8, 193–204 (2008)

  88. 88.

    , & DNA repair deficiency as a therapeutic target in cancer. Curr. Opin. Genet. Dev. 18, 80–86 (2008)

  89. 89.

    et al. The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev. 23, 1895–1909 (2009)

  90. 90.

    et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005)

  91. 91.

    et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005)References 90 and 91 document the potential of personalized cancer treatment, based on the exceptional sensitivity of tumour cells defective in BRCA1/BRCA2-dependent HR towards small molecule inhibitors of PARP1; these studies support the principle of synthetic-lethal relationships between complementary DDR pathways.

  92. 92.

    et al. Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics. Int. J. Cancer 119, 2784–2794 (2006)

  93. 93.

    et al. ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002)

  94. 94.

    & Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc. Drug Rev. 25, 235–260 (2007)

  95. 95.

    Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr. Opin. Pharmacol. 8, 96–103 (2008)

  96. 96.

    , , & The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo. Nature Med. 5, 335–339 (1999)

  97. 97.

    DNA damage, vascular senescence and atherosclerosis. J. Mol. Med. 86, 1033–1043 (2008)

  98. 98.

    et al. Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nature Cell Biol. 7, 493–500 (2005)

  99. 99.

    et al. Evidence that the Nijmegen breakage syndrome protein, an early sensor of double-strand DNA breaks (DSB), is involved in HIV-1 post-integration repair by recruiting the ataxia telangiectasia-mutated kinase in a process similar to, but distinct from, cellular DSB repair. Virol. J. 5, 11 (2008)

  100. 100.

    et al. Targeted gene addition into a specified location in the human genome using designed zinc finger nucleases. Proc. Natl Acad. Sci. USA 104, 3055–3060 (2007)

  101. 101.

    The DNA-damage response: new molecular insights and new approaches to cancer therapy. Biochem. Soc. Trans. 37, 483–494 (2009)

Download references

Acknowledgements

We thank S. Polo and P. Huertas for advice, and K. Dry for expert help with the text and figures. The S.P.J. laboratory is supported by grants from Cancer Research UK, the European Commission (projects GENICA and DNA Repair), the Wellcome Trust and the Biotechnology and Biological Sciences Research Council. The J.B. laboratory is supported by grants from the Danish Cancer Society, the Danish National Research Foundation and the European Commission (projects GENICA, Active p53, TRIREME and DNA Repair).

Author Contributions S.P.J. and J.B. conceived of and wrote all aspects of this article.

Author information

Affiliations

  1. The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK

    • Stephen P. Jackson
  2. Danish Cancer Society, Centre for Genotoxic Stress Research, Strandboulevarden 49, DK-2100 Copenhagen, Denmark, and Institute of Molecular Genetics, CZ-14220 Prague, Czech Republic

    • Jiri Bartek

Authors

  1. Search for Stephen P. Jackson in:

  2. Search for Jiri Bartek in:

Corresponding author

Correspondence to Stephen P. Jackson.

Supplementary information

PDF files

  1. 1.

    Supplementary Table

    This file contains Supplementary Table 1.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nature08467

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.