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DNA repair pathways as targets for cancer therapy

Key Points

  • Several cancer chemotherapy drugs work by producing excessive DNA damage that causes cell death directly or following DNA replication. Survival is promoted through repair of these lesions by a number of DNA repair pathways.

  • The efficacy of anticancer drugs is highly influenced by cellular DNA repair capacity. Inhibitors of DNA repair increase the efficacy of DNA-damaging anticancer drugs in preclinical models. Small-molecule inhibitors of DNA repair have been combined with conventional chemotherapy drugs in several phase I–II clinical trials.

  • Tumour development can be associated with perturbed DNA damage response and repair pathways. This perturbation results in reduced DNA repair capacity and increased genetic instability in tumour cells. Defects in one DNA repair pathway can be compensated for by other pathways. Such compensating pathways can be identified in synthetic lethality screens and then specifically targeted for treatment of DNA repair-defective tumours.

  • Evidence indicates that inhibitors of DNA repair pathways can work as single agents for the targeted treatment of DNA repair-defective cancers. This hypothesis is currently being tested in phase II trials in which patients with breast or ovarian cancers that are defective in homologous recombination are being treated with a poly(ADP-ribose) polymerase inhibitor.

  • Tumours often exhibit replication stress as a consequence of oncogene-induced growth signals or hypoxia-induced replication arrest. We propose that DNA repair inhibitors could be used to prevent the repair of replication lesions present in tumour cells and convert them into fatal replication lesions that specifically kill cancer cells.

Abstract

DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

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Figure 1: Overview of DNA repair pathways involved in repairing toxic DNA lesions formed by cancer treatments.
Figure 2: Synthetic lethal interactions to identify molecular targets for inhibitors of DNA repair.

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References

  1. Hsiang, Y. H., Lihou, M. G. & Liu, L. F. Arrest of replication forks by drug-stabilized topoisomerase I — DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077–5082 (1989).

    CAS  PubMed  Google Scholar 

  2. Markovits, J. et al. Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells. Cancer Res. 47, 2050–2055 (1987).

    CAS  PubMed  Google Scholar 

  3. Ikegami, S. et al. Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-α. Nature 275, 458–460 (1978).

    CAS  PubMed  Google Scholar 

  4. Bianchi, V., Pontis, E. & Reichard, P. Changes of deoxyribonucleoside triphosphate pools induced by hydroxyurea and their relation to DNA synthesis. J. Biol. Chem. 261, 16037–16042 (1986).

    CAS  PubMed  Google Scholar 

  5. Lundin, C. et al. Different roles for nonhomologous end joining and homologous recombination following replication arrest in mammalian cells. Mol. Cell Biol. 22, 5869–5878 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Saintigny, Y. et al. Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J. 20, 3861–3870 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Swann, P. F. et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273, 1109–1111 (1996).

    CAS  PubMed  Google Scholar 

  8. Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nature Rev. Mol. Cell Biol. 3, 430–440 (2002).

    CAS  Google Scholar 

  9. Painter, R. B. & Cleaver, J. E. Repair replication in HeLa cells after large doses of x-irradiation. Nature 216, 369–370 (1967).

    CAS  PubMed  Google Scholar 

  10. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).

    CAS  PubMed  Google Scholar 

  11. Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J. & Lukas, J. The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847 (2001). This paper describes the molecular mechanism by which ATM rapidly inactivates DNA synthesis following ionizing radiation.

    CAS  PubMed  Google Scholar 

  12. Cliby, W. A. et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 17, 159–169 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Taylor, A. M. et al. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258, 427–429 (1975).

    CAS  PubMed  Google Scholar 

  14. Sargent, R. G., Brenneman, M. A. & Wilson, J. H. Repair of site-specific double-strand breaks in a mammalian chromosome by homologous and illegitimate recombination. Mol. Cell Biol. 17, 267–277 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Arnaudeau, C., Lundin, C. & Helleday, T. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J. Mol. Biol. 307, 1235–1245 (2001).

    CAS  PubMed  Google Scholar 

  16. Sharma, R. A. & Dianov, G. L. Targeting base excision repair to improve cancer therapies. Mol. Aspects Med. 28, 345–374 (2007).

    CAS  PubMed  Google Scholar 

  17. Huang, J. C., Svoboda, D. L., Reardon, J. T. & Sancar, A. Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5′ and the 6th phosphodiester bond 3′ to the photodimer. Proc. Natl Acad. Sci. USA 89, 3664–3668 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sugasawa, K. et al. A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev. 15, 507–521 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sedgwick, B. Repairing DNA-methylation damage. Nature Rev. Mol. Cell Biol. 5, 148–157 (2004).

    CAS  Google Scholar 

  20. Lindahl, T., Demple, B. & Robins, P. Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase. EMBO J. 1, 1359–1363 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Duncan, T. et al. Reversal of DNA alkylation damage by two human dioxygenases. Proc. Natl Acad. Sci. USA 99, 16660–16665 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Karran, P. & Marinus, M. G. Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 296, 868–869 (1982).

    CAS  PubMed  Google Scholar 

  23. Yoshioka, K., Yoshioka, Y. & Hsieh, P. ATR kinase activation mediated by MutSα and MutLα in response to cytotoxic O6-methylguanine adducts. Mol. Cell 22, 501–510 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Fram, R. J., Cusick, P. S., Wilson, J. M. & Marinus, M. G. Mismatch repair of cis-diamminedichloroplatinum(II)-induced DNA damage. Mol. Pharmacol. 28, 51–55 (1985).

    CAS  PubMed  Google Scholar 

  25. Masutani, C., Kusumoto, R., Iwai, S. & Hanaoka, F. Mechanisms of accurate translesion synthesis by human DNA polymerase η. EMBO J. 19, 3100–3109 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Vaisman, A., Masutani, C., Hanaoka, F. & Chaney, S. G. Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase η. Biochemistry 39, 4575–4580 (2000).

    CAS  PubMed  Google Scholar 

  27. Fukui, T. et al. Distinct roles of DNA polymerases δ and ɛ at the replication fork in Xenopus egg extracts. Genes Cells 9, 179–191 (2004).

    CAS  PubMed  Google Scholar 

  28. Pursell, Z. F., Isoz, I., Lundstrom, E. B., Johansson, E. & Kunkel, T. A. Yeast DNA polymerase ɛ participates in leading-strand DNA replication. Science 317, 127–130 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lehmann, A. R. Translesion synthesis in mammalian cells. Exp. Cell Res. 312, 2673–2676 (2006).

    CAS  PubMed  Google Scholar 

  30. Sorensen, C. S. et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nature Cell Biol. 7, 195–201 (2005).

    CAS  PubMed  Google Scholar 

  31. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006). References 32 and 33 show that oncogenes induce replication lesions in premalignant cancer cells that in turn activate senescence as a tumour barrier.

    CAS  PubMed  Google Scholar 

  34. Arnaudeau, C., Tenorio Miranda, E., Jenssen, D. & Helleday, T. Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells. Mutat. Res. DNA Repair 461, 221–228 (2000).

    CAS  PubMed  Google Scholar 

  35. Helleday, T., Lo, J., van Gent, D. C. & Engelward, B. P. DNA double-strand break repair: From mechanistic understanding to cancer treatment. DNA Repair (Amst.) 6, 923–935 (2007).

    CAS  Google Scholar 

  36. Patel, K. J. & Joenje, H. Fanconi anemia and DNA replication repair. DNA Repair (Amst.) 6, 885–890 (2007).

    CAS  Google Scholar 

  37. Hanada, K. et al. The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nature Struct. Mol. Biol. 14, 1096–1104 (2007).

    CAS  Google Scholar 

  38. Karow, J. K., Constantinou, A., Li, J. L., West, S. C. & Hickson, I. D. The Bloom's syndrome gene product promotes branch migration of holliday junctions. Proc. Natl Acad. Sci. USA 97, 6504–6508 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lebel, M., Spillare, E. A., Harris, C. C. & Leder, P. The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J. Biol. Chem. 274, 37795–37799 (1999).

    CAS  PubMed  Google Scholar 

  40. Constantinou, A. et al. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO Rep. 1, 80–84 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu, L. & Hickson, I. D. DNA helicases required for homologous recombination and repair of damaged replication forks. Annu. Rev. Genet. 40, 279–306 (2006).

    CAS  PubMed  Google Scholar 

  42. Niedzwiedz, W. et al. The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol. Cell 15, 607–620 (2004).

    CAS  PubMed  Google Scholar 

  43. Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003).

    CAS  PubMed  Google Scholar 

  44. Chen, X. B. et al. Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. Mol. Cell 8, 1117–1127 (2001).

    CAS  PubMed  Google Scholar 

  45. Hinz, J. M., Nham, P. B., Urbin, S. S., Jones, I. M. & Thompson, L. H. Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis. Nucleic Acids Res. 35, 3733–3740 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Thompson, L. H. Strategies for cloning mammalian DNA repair genes. Methods Mol. Biol. 113, 57–85 (1999).

    CAS  PubMed  Google Scholar 

  47. Chabner, B. A. & Roberts, T. G. Jr. Chemotherapy and the war on cancer. Nature Rev. Cancer 5, 65–72 (2005).

    CAS  Google Scholar 

  48. Stevens, M. F. et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 47, 5846–5852 (1987).

    CAS  PubMed  Google Scholar 

  49. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005). References 48 and 49 demonstrate the timescale required from drug discovery in the laboratory to the demonstration of improved survival in patients in a randomized phase III clinical trial, in this case for temozolomide as a radiosensitizer.

    CAS  PubMed  Google Scholar 

  50. Dolan, M. E. & Pegg, A. E. O6-Benzylguanine and its role in chemotherapy. Clin. Cancer Res. 3, 837–847 (1997).

    CAS  PubMed  Google Scholar 

  51. Gerson, S. L., Berger, N. A., Arce, C., Petzold, S. J. & Willson, J. K. Modulation of nitrosourea resistance in human colon cancer by O6-methylguanine. Biochem. Pharmacol. 43, 1101–1107 (1992).

    CAS  PubMed  Google Scholar 

  52. Middleton, M. R. & Margison, G. P. Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway. Lancet Oncol. 4, 37–44 (2003).

    CAS  PubMed  Google Scholar 

  53. Ranson, M. et al. Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 12, 1577–1584 (2006).

    CAS  PubMed  Google Scholar 

  54. Quinn, J. A. et al. Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 23, 7178–7187 (2005).

    CAS  PubMed  Google Scholar 

  55. Khan, O. & Middleton, M. R. The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors. Expert Opin. Investig. Drugs 16, 1573–1584 (2007).

    CAS  PubMed  Google Scholar 

  56. Durkacz, B. W., Omidiji, O., Gray, D. A. & Shall, S. (ADP-ribose)n participates in DNA excision repair. Nature 283, 593–596 (1980). This study was first to demonstrate that PARP inhibitors can be used to increase the toxicity of DNA-damaging agents.

    CAS  PubMed  Google Scholar 

  57. Yang, Y. G., Cortes, U., Patnaik, S., Jasin, M. & Wang, Z. Q. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene 23, 3872–3882 (2004).

    CAS  PubMed  Google Scholar 

  58. Ahel, I. et al. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81–85 (2008).

    CAS  PubMed  Google Scholar 

  59. Rosenberg, B., VanCamp, L., Trosko, J. E. & Mansour, V. H. Platinum compounds: a new class of potent antitumour agents. Nature 222, 385–386 (1969).

    CAS  PubMed  Google Scholar 

  60. Kubo, S. et al. Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines. J. Cancer Res. Clin. Oncol. 118, 244–248 (1992).

    CAS  PubMed  Google Scholar 

  61. Miknyoczki, S. J. et al. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol. Cancer Ther. 2, 371–382 (2003).

    CAS  PubMed  Google Scholar 

  62. Robins, H. I. et al. Phase I trial of intravenous thymidine and carboplatin in patients with advanced cancer. J. Clin. Oncol. 17, 2922–2931 (1999).

    CAS  PubMed  Google Scholar 

  63. Donawho, C. K. et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13, 2728–2737 (2007).

    CAS  PubMed  Google Scholar 

  64. Gifford, G., Paul, J., Vasey, P. A., Kaye, S. B. & Brown, R. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin. Cancer Res. 10, 4420–4426 (2004).

    CAS  PubMed  Google Scholar 

  65. Plumb, J. A., Strathdee, G., Sludden, J., Kaye, S. B. & Brown, R. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 60, 6039–6044 (2000).

    CAS  PubMed  Google Scholar 

  66. Rabik, C. A. & Dolan, M. E. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 33, 9–23 (2007).

    CAS  PubMed  Google Scholar 

  67. Olaussen, K. A. et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N. Engl. J. Med. 355, 983–991 (2006).

    CAS  PubMed  Google Scholar 

  68. Tsao, M. S. et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J. Clin. Oncol. 25, 5240–5247 (2007).

    PubMed  Google Scholar 

  69. Jiang, H. & Yang, L. Y. Cell cycle checkpoint abrogator UCN-01 inhibits DNA repair: association with attenuation of the interaction of XPA and ERCC1 nucleotide excision repair proteins. Cancer Res. 59, 4529–4534 (1999).

    CAS  PubMed  Google Scholar 

  70. Matthews, D. J. et al. Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 6, 104–110 (2007).

    CAS  PubMed  Google Scholar 

  71. Syljuasen, R. G. et al. Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol. Cell Biol. 25, 3553–3562 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hartley, K. O. et al. DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82, 849–856 (1995).

    CAS  PubMed  Google Scholar 

  73. Blunt, T. et al. Defective DNA-dependent protein kinase activity is linked to VDJ recombination and DNA repair defects associated with the murine scid mutation. Cell 80, 813–823 (1995). This paper identifies DNAPK and shows that it can be used as a target to increase toxicity following ionizing radiation.

    CAS  PubMed  Google Scholar 

  74. Monfar, M. et al. Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol. Cell Biol. 15, 326–337 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wipf, P. & Halter, R. J. Chemistry and biology of wortmannin. Org. Biomol. Chem. 3, 2053–2061 (2005).

    CAS  PubMed  Google Scholar 

  76. Leahy, J. J. et al. Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg. Med. Chem. Lett. 14, 6083–6087 (2004).

    CAS  PubMed  Google Scholar 

  77. Zhao, Y. et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354–5362 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase. Nature 434, 913–917 (2005). References 78 and 79 show that PARP inhibitors can be used to selectively kill BRCA1- or BRCA2-defective tumours.

    CAS  PubMed  Google Scholar 

  80. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    CAS  PubMed  Google Scholar 

  81. Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).

    CAS  PubMed  Google Scholar 

  82. Patel, K. J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).

    CAS  PubMed  Google Scholar 

  83. Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A. R. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes Dev. 17, 3017–3022 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Helleday, T., Bryant, H. E. & Schultz, N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 4, 1176–1178 (2005).

    CAS  PubMed  Google Scholar 

  85. Schultz, N., Lopez, E., Saleh-Gohari, N. & Helleday, T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 31, 4959–4964 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Fisher, A., Hochegger, H., Takeda, S. & Caldecott, K. W. Poly (ADP-ribose) polymerase-1 accelerates single-strand break repair in concert with poly (ADP-ribose) glycohydrolase. Mol. Cell Biol. 27, 5597–5605 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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  PubMed  Google Scholar 

  88. Bryant, H. E. & Helleday, T. Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Nucleic Acids Res. 34, 1685–1691 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kennedy, R. D. et al. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J. Clin. Invest. 117, 1440–1449 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    CAS  PubMed  Google Scholar 

  91. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  93. Kinzler, K. W. & Vogelstein, B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 386, 761–763 (1997).

    CAS  PubMed  Google Scholar 

  94. Schmitt, C. A. Senescence, apoptosis and therapy — cutting the lifelines of cancer. Nature Rev. Cancer 3, 286–295 (2003).

    CAS  Google Scholar 

  95. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    CAS  PubMed  Google Scholar 

  96. Vousden, K. H. & Lane, D. P. p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007).

    CAS  Google Scholar 

  97. Mariani, B. D. & Schimke, R. T. Gene amplification in a single cell cycle in Chinese hamster ovary cells. J. Biol. Chem. 259, 1901–1910 (1984).

    CAS  PubMed  Google Scholar 

  98. Rambach, W. A., Cooper, J. A. & Alt, H. L. Effect of hypoxia on DNA synthesis in the bone marrow and spleen of the rat. Science 119, 380–381 (1954).

    CAS  PubMed  Google Scholar 

  99. Hammond, E. M., Denko, N. C., Dorie, M. J., Abraham, R. T. & Giaccia, A. J. Hypoxia links ATR and p53 through replication arrest. Mol. Cell Biol. 22, 1834–1843 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Hammond, E. M., Dorie, M. J. & Giaccia, A. J. ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J. Biol. Chem. 278, 12207–12213 (2003).

    CAS  PubMed  Google Scholar 

  101. Gibson, S. L., Bindra, R. S. & Glazer, P. M. Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. Cancer Res. 65, 10734–10741 (2005).

    CAS  PubMed  Google Scholar 

  102. Bindra, R. S., Crosby, M. E. & Glazer, P. M. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 26, 249–260 (2007).

    CAS  PubMed  Google Scholar 

  103. Rockwell, S., Yuan, J., Peretz, S. & Glazer, P. M. Genomic instability in cancer. Novartis Found. Symp. 240, 133–142; discussion 142–151 (2001).

    CAS  PubMed  Google Scholar 

  104. Reynolds, T. Y., Rockwell, S. & Glazer, P. M. Genetic instability induced by the tumor microenvironment. Cancer Res. 56, 5754–5757 (1996).

    CAS  PubMed  Google Scholar 

  105. Hammond, E. M., Dorie, M. J. & Giaccia, A. J. Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res. 64, 6556–6562 (2004).

    CAS  PubMed  Google Scholar 

  106. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Google Scholar 

  107. Di Micco, R., Fumagalli, M. & di Fagagna, F. Breaking news: high-speed race ends in arrest — how oncogenes induce senescence. Trends Cell Biol. 17, 529–536 (2007).

    CAS  PubMed  Google Scholar 

  108. Giannini, G. et al. Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep. 3, 248–254 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Shor, E. et al. Mutations in homologous recombination genes rescue top3 slow growth in Saccharomyces cerevisiae. Genetics 162, 647–662 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wallis, J. W., Chrebet, G., Brodsky, G., Rolfe, M. & Rothstein, R. A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase. Cell 58, 409–419 (1989).

    CAS  PubMed  Google Scholar 

  111. Tong, A. H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364–2368 (2001). This study show how systematic genetic analysis can be performed to produce a global map of gene function.

    CAS  PubMed  Google Scholar 

  112. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    CAS  PubMed  Google Scholar 

  113. Hiramoto, T. et al. Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer. Oncogene 18, 3422–3426 (1999).

    CAS  PubMed  Google Scholar 

  114. Schoenmakers, E. F., Huysmans, C. & Van de Ven, W. J. Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Cancer Res. 59, 19–23 (1999).

    CAS  PubMed  Google Scholar 

  115. Wong, A. K. et al. Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17, 2279–2285 (1998).

    CAS  PubMed  Google Scholar 

  116. Riballo, E. et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr. Biol. 9, 699–702 (1999).

    CAS  PubMed  Google Scholar 

  117. Moshous, D. et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Invest. 111, 381–387 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).

    CAS  PubMed  Google Scholar 

  119. Lipkin, S. M. et al. Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. Hum. Mutat. 17, 389–396 (2001).

    CAS  PubMed  Google Scholar 

  120. de la Chapelle, A. Genetic predisposition to colorectal cancer. Nature Rev. Cancer 4, 769–780 (2004).

    CAS  Google Scholar 

  121. German, J., Bloom, D. & Passarge, E. Bloom's syndrome. V. Surveillance for cancer in affected families. Clin. Genet. 12, 162–168 (1977).

    CAS  PubMed  Google Scholar 

  122. Mohaghegh, P. & Hickson, I. D. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Mol. Genet. 10, 741–746 (2001).

    CAS  PubMed  Google Scholar 

  123. Vorechovsky, I. et al. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nature Genet. 17, 96–99 (1997).

    CAS  PubMed  Google Scholar 

  124. Menisser-de Murcia, J., Mark, M., Wendling, O., Wynshaw-Boris, A. & de Murcia, G. Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during development. Mol. Cell Biol. 21, 1828–1832 (2001).

    CAS  PubMed  Google Scholar 

  125. Bryant, H. E., Ying, S. & Helleday, T. Homologous recombination is involved in repair of chromium-induced DNA damage in mammalian cells. Mutat. Res. 599, 116–123 (2006).

    CAS  PubMed  Google Scholar 

  126. Matsuura, S. et al. Positional cloning of the gene for Nijmegen breakage syndrome. Nature Genet. 19, 179–181 (1998).

    CAS  PubMed  Google Scholar 

  127. Levine, A. J., Momand, J. & Finlay, C. A. The p53 tumour suppressor gene. Nature 351, 453–456 (1991).

    CAS  PubMed  Google Scholar 

  128. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li–Fraumeni syndrome. Science 286, 2528–2531 (1999).

    CAS  PubMed  Google Scholar 

  129. Cleaver, J. E. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nature Rev. Cancer 5, 564–573 (2005).

    CAS  Google Scholar 

  130. Cheng, L., Sturgis, E. M., Eicher, S. A., Spitz, M. R. & Wei, Q. Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer 94, 393–397 (2002).

    CAS  PubMed  Google Scholar 

  131. Taniguchi, T. & D'Andrea, A. D. Molecular pathogenesis of Fanconi anemia: recent progress. Blood 107, 4223–4233 (2006).

    CAS  PubMed  Google Scholar 

  132. Wang, L., Patel, U., Ghosh, L. & Banerjee, S. DNA polymerase β mutations in human colorectal cancer. Cancer Res. 52, 4824–4827 (1992).

    CAS  PubMed  Google Scholar 

  133. Zheng, L. et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Med. 13, 812–819 (2007).

    CAS  PubMed  Google Scholar 

  134. Koster, D. A., Palle, K., Bot, E. S. M., Bjornsti, M.-A. and Dekker, N. H. Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448, 213–217 (2007).

    CAS  PubMed  Google Scholar 

  135. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265, 2088–2090 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the Medical Research Council, The Swedish Research Council, The Swedish Cancer Society, The Swedish Children's Cancer Foundation, The Swedish Pain Relief Foundation and Cancer Research UK for financial support. We recognize that we were unable to cover all aspects of DNA repair in cancer in this Review. We apologize to those whom we have been unable to cite owing to space constraints.

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Correspondence to Thomas Helleday.

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Competing interests

Patents regarding targeting DNA repair have been filed by the University of Sheffield's and University of Oxford's technology transfer companies with Thomas Helleday as named inventor.

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Supplementary information S1 (Table)

Synthetic lethal interactions of S. cerevisiae genes that are homologous to human DNA repair and checkpoint genes implicated in cancer. (PDF 710 kb)

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DATABASES

ClinicalTrials.gov

NCT00475917

NCT00526617

National Cancer Institute

breast cancer

ovarian cancer

National Cancer Institute Drug Dictionary

5-fluorouracil

6-thioguanine

bleomycin

carboplatin

chlorambucil

cisplatin

cyclophosphamide

dacarbazine

decitabine

etoposide

gemcitabine

hydroxyurea

melphalan

mitomycin C

oxaliplatin

temozolomide

UCN-01

XL844

FURTHER INFORMATION

Thomas Helleday's homepage

Decitabine and Carboplatin in Relapsed Ovarian Cancer

Glossary

Alkylating agents

Electrophilic compounds that are reactive either directly or following metabolism and bind covalently to electron-rich atoms in DNA bases (that is, oxygen and nitrogen).

Antimetabolites

Compounds with similar chemical structures to nucleotide metabolites that interfere with nucleotide biosynthesis or are incorporated into DNA.

Non-homologous end joining

Connection and resealing of the two ends of a DNA double-strand break without the need for sequence homology between the ends.

Homologous recombination

A process that can copy a DNA sequence from an intact DNA molecule (often the newly synthesized sister chromatid) to repair or bypass replication lesions.

Base-excision repair

A repair pathway that replaces missing or modified DNA bases, such as those produced by alkylating agents or in spontaneously degraded DNA, with the correct DNA base.

Nucleotide-excision repair

A process that removes large DNA adducts or base modifications that distort the double helix and uses the opposite strand as template for repair.

Alkyltransferases

A class of enzymes that directly reverse DNA base modifications that are induced by alkylating agents by transferring the alkyl group from the base onto the protein.

DNA dioxygenases

A class of enzymes that directly reverse DNA base methylations through an oxidation mechanism. The human DNA dioxygenase ABH2 is thought to act at replication forks.

Mismatch repair

A process that acts during DNA replication to correct base-pairing errors made by the DNA polymerases.

Translesion synthesis

A mechanism during DNA replication in which the standard DNA polymerase is temporarily exchanged for a specialized polymerase that can synthesize DNA across base damage on the template strand.

Fanconi anaemia repair pathway

Proteins of this pathway, including BRCA2, are mutated in the hereditary disorder Fanconi anaemia (FA), resulting in hypersensitivity to inter-strand crosslinks. Evidence suggests that the FA pathway promotes the repair of stalled replication forks, possibly by activating HR and facilitating ATR- and ATM-dependent checkpoint signalling.

Endonuclease-mediated repair

A repair pathway that introduces a DNA single-strand break in a DNA structure to facilitate continuous repair.

RecQ-mediated repair

A repair pathway that unwinds complex DNA structure to facilitate repair.

Therapeutic index

The therapeutic index describes the ability of a treatment strategy to kill cancer cells in preference to cells in normal tissues.

Synthetic lethality

A genetic phenomenon in which the combination of two otherwise non-lethal mutations results in an inviable cell. Synthetic lethal phenotypes are indicative of an interaction between the products of the two mutant genes within the cell.

Biomarkers

A molecule or substance whose detection indicates a particular disease state or treatment response.

Hypoxia

A subnormal concentration of oxygen. In cancer tissue, hypoxia is often the result of abnormal vasculature.

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Helleday, T., Petermann, E., Lundin, C. et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8, 193–204 (2008). https://doi.org/10.1038/nrc2342

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