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The DNA damage response and cancer therapy


Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.

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Figure 1: A panoply of DNA repair mechanisms maintains genomic stability.
Figure 2: Genomic scars in cancer.


  1. 1

    Boveri, T. Zur Frage der Entstehung Maligner Tumoren (Gustav Fischer, 1914).

    Google Scholar 

  2. 2

    Boveri, T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121, 1–84 (2008). A translation of Boveri's original work that proposed the hypothesis that a form of genomic dysregulation characterizes tumour cells.

    Article  Google Scholar 

  3. 3

    Ciccia, A. & Elledge, S. J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Phillips, D. H., Hewer, A., Martin, C. N., Garner, R. C. & King, M. M. Correlation of DNA adduct levels in human lung with cigarette smoking. Nature 336, 790–792 (1988).

    ADS  CAS  Article  Google Scholar 

  6. 6

    David, S. S., O'Shea, V. L. & Kundu, S. Base-excision repair of oxidative DNA damage. Nature 447, 941–950 (2007).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Nakabeppu, Y. et al. Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. Biol. Chem. 387, 373–379 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Cleaver, J. E., Lam, E. T. & Revet, I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nature Rev. Genet. 10, 756–768 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Moynahan, M. E. & Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nature Rev. Mol. Cell Biol. 11, 196–207 (2010).

    CAS  Article  Google Scholar 

  10. 10

    Lieber, M. R. NHEJ and its backup pathways in chromosomal translocations. Nature Struct. Mol. Biol. 17, 393–395 (2010).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

    Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    MathSciNet  CAS  Article  Google Scholar 

  14. 14

    Bell, O., Tiwari, V. K., Thoma, N. H. & Schubeler, D. Determinants and dynamics of genome accessibility. Nature Rev. Genet. 12, 554–564 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Warmerdam, D. O. & Kanaar, R. Dealing with DNA damage: relationships between checkpoint and repair pathways. Mutat. Res. 704, 2–11 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  18. 18

    Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008). References 18 and 19 describes how oncogenes are able to induce the DDR early in oncogenesis.

    ADS  CAS  Article  Google Scholar 

  20. 20

    Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nature Rev. Cancer 4, 814–819 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Banerjee, S., Kaye, S. B. & Ashworth, A. Making the best of PARP inhibitors inovarian cancer. Nature Rev. Clin. Oncol. 7, 508–519 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Friboulet, L. et al. Molecular characteristics of ERCC1-negative versus ERCC1-positive tumors in resected NSCLC. Clin. Cancer Res. 17, 5562–5572 (2011).

    CAS  Article  Google Scholar 

  23. 23

    Weller, M. et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nature Rev. Neurol. 6, 39–51 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Pommier, Y., Leo, E., Zhang, H. & Marchand, C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17, 421–433 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nature Rev. Cancer 10, 293–301 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Zaremba, T. & Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med. Chem. 7, 515–523 (2007).

    CAS  Article  Google Scholar 

  27. 27

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

    ADS  CAS  Article  Google Scholar 

  28. 28

    Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). References 27 and 28 describe the synthetic lethal interaction between BRCA mutations and PARP inhibition.

    ADS  CAS  Article  Google Scholar 

  29. 29

    Lord, C. J. & Ashworth, A. Targeted therapy for cancer using PARP inhibitors. Curr. Opin. Pharmacol. 8, 363–369 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Dobzhansky, T. Genetics of natural populations. Xiii. Recombination and variability in populations of drosophila pseudoobscura . Genetics 31, 269–290 (1946).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lucchesi, J. C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster . Genetics 59, 37–44 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W. & Friend, S. H. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997).

    ADS  CAS  Article  Google Scholar 

  33. 33

    Kaelin, W. G. Jr. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med. 1, 99 (2009).

    Article  Google Scholar 

  34. 34

    Issaeva, N. et al. 6-Thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res. 70, 6268–6276 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Martin, S. A. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17, 235–248 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Martin, S. A., Hewish, M., Sims, D., Lord, C. J. & Ashworth, A. Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res. 71, 1836–1848 (2011).

    CAS  Article  Google Scholar 

  37. 37

    Martin, S. A. et al. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2 . EMBO Mol. Med. 1, 323–337 (2009).

    CAS  Article  Google Scholar 

  38. 38

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009). This article describes the results of the first clinical trial to demonstrate the clinical potential of a synthetic lethal approach for therapy.

    CAS  Article  Google Scholar 

  39. 39

    Balmaña, J., Domchek, S. M., Tutt, A. & Garber, J. E. Stumbling blocks on the path to personalized medicine in breast cancer: the case of PARP inhibitors for BRCA1/2-associated cancers. Cancer Discov. 1, 29–34 (2011).

    Article  Google Scholar 

  40. 40

    Mendeleyev, J., Kirsten, E., Hakam, A., Buki, K. G. & Kun, E. Potential chemotherapeutic activity of 4-iodo-3-nitrobenzamide. Metabolic reduction to the 3-nitroso derivative and induction of cell death in tumor cells in culture. Biochem. Pharmacol. 50, 705–714 (1995).

    CAS  Article  Google Scholar 

  41. 41

    Liu, X. et al. Iniparib non-selectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin. Cancer Res. advance ahead of print (29 November 2011).

  42. 42

    McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    CAS  Article  Google Scholar 

  43. 43

    Peasland, A. et al. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br. J. Cancer 105, 372–381 (2011).

    CAS  Article  Google Scholar 

  44. 44

    Murai, J. et al. The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Mol. Cell. Biol. 31, 2462–2469 (2011).

    CAS  Article  Google Scholar 

  45. 45

    Moskwa, P. et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol. Cell 41, 210–220 (2011).

    CAS  Article  Google Scholar 

  46. 46

    Johnson, N. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nature Med. 17, 875–882 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Akamatsu, Y. & Jasin, M. Role for the mammalian Swi5−Sfr1 complex in DNA strand break repair through homologous recombination. PLoS Genet. 6, e1001160 (2010).

    Article  Google Scholar 

  48. 48

    Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    CAS  Article  Google Scholar 

  49. 49

    Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011). An important paper suggesting that ETS gene fusions may confer PARP-inhibitor sensitivity in prostate cancer.

    CAS  Article  Google Scholar 

  50. 50

    Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).

    ADS  CAS  Article  Google Scholar 

  51. 51

    Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008). References 50 and 51 are the first demonstrations of synthetic lethal resistance to PARP inhibitors and platinum drugs in BRCA -mutant cells.

    ADS  CAS  Article  Google Scholar 

  52. 52

    Sakai, W. et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 69, 6381–6386 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Swisher, E. M. et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 68, 2581–2586 (2008).

    CAS  Article  Google Scholar 

  54. 54

    Norquist, B. et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol. 29, 3008–3015 (2011).

    CAS  Article  Google Scholar 

  55. 55

    Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079–17084 (2008).

    ADS  CAS  Article  Google Scholar 

  56. 56

    Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA- mutated breast cancers. Nature Struct. Mol. Biol. 17, 688–695 (2010).

    CAS  Article  Google Scholar 

  57. 57

    Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    CAS  Article  Google Scholar 

  58. 58

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

    ADS  CAS  Article  Google Scholar 

  59. 59

    Galanty, Y. et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935–939 (2009).

    ADS  CAS  Article  Google Scholar 

  60. 60

    Soucy, T. A. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736 (2009). This paper provides proof of the concept that targeting additional elements of the DDR and replication machinery, such as neddylation complexes, could provide an alternative approach to cancer therapy.

    ADS  CAS  Article  Google Scholar 

  61. 61

    Lansdorp, P. M. Immortal strands? Give me a break. Cell 129, 1244–1247 (2007).

    CAS  Article  Google Scholar 

  62. 62

    Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).

    ADS  CAS  Article  Google Scholar 

  63. 63

    Zhang, M., Atkinson, R. L. & Rosen, J. M. Selective targeting of radiation-resistant tumor-initiating cells. Proc. Natl Acad. Sci. USA 107, 3522–3527 (2010).

    ADS  CAS  Article  Google Scholar 

  64. 64

    Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    ADS  CAS  Article  Google Scholar 

  65. 65

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

    ADS  CAS  Article  Google Scholar 

  66. 66

    Mantoni, T. S., Lunardi, S., Al-Assar, O., Masamune, A. & Brunner, T. B. Pancreatic stellate cells radioprotect pancreatic cancer cells through beta 1-integrin signaling. Cancer Res. 71, 3453–3458 (2011).

    CAS  Article  Google Scholar 

  67. 67

    Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. Science 331, 1553–1558 (2011).

    ADS  CAS  Article  Google Scholar 

  68. 68

    Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009).

    ADS  CAS  Article  Google Scholar 

  69. 69

    Barber, L. J. et al. Comprehensive genomic analysis of a BRCA2 deficient human pancreatic cancer. PLoS ONE 6, e21639 (2011).

    ADS  CAS  Article  Google Scholar 

  70. 70

    Graeser, M. et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin. Cancer Res. 16, 6159–6168 (2010).

    CAS  Article  Google Scholar 

  71. 71

    Polo, S. E. & Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

    CAS  Article  Google Scholar 

  72. 72

    Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    ADS  CAS  Article  Google Scholar 

  73. 73

    Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).

    CAS  Article  Google Scholar 

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We thank Cancer Research UK, The Wellcome Trust, Breakthrough Breast Cancer, AACR, The Komen Foundation, The Breast Cancer Research Foundation, the European Union and The Breast Cancer Campaign for funding the work in our laboratory. We also acknowledge NHS funding to the Royal Marsden Hospital NIHR Biomedical Research Centre.

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Correspondence to Christopher J. Lord or Alan Ashworth.

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Competing interests

C.J.L. and A.A. are named inventors on patents describing the use of PARP inhibitors and may stand to gain under the ICR, 'Rewards to Inventors Scheme'.

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Lord, C., Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

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