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DNA Double Strand Break Repair: Mechanisms and Therapeutic Potential

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The DNA Damage Response: Implications on Cancer Formation and Treatment

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Abstract

DNA double strand breaks are widely considered to be the most cytotoxic form of DNA damage. They can be induced by exposure to exogenous agents such as ionizing radiation and topoisomerase poisons and can also occur naturally due to replication fork collapse and other cellular processes. DNA double strand breaks are also produced in the immune system as a consequence of V(D)J and class switch recombination. Here, we will review the major pathways for the detection and repair of DNA double strand breaks in human cells, namely non-homologous end joining and homologous recombination/homology-directed repair. We will also discuss how a better understanding of these pathways could lead to new, more targeted approaches for cancer therapy.

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Abbreviations

A-T:

Ataxia-Telangiectasia

ATM:

ataxia-telangiectasia mutated

ATR:

ATM- and Rad3-related

BRCA:

Breast and ovarian cancer susceptibility allele

CSR:

class switch recombination

ds:

double-stranded

DNA-PK:

DNA-dependent protein kinase

DNA-PKcs:

catalytic subunit of the DNA-dependent protein kinase

DSB:

DNA double strand break

DSBR:

DNA double strand break repair

FANCD1:

Fanconi Anemia complementary group D1

FA:

Fanconi Anemia

HDR:

homology directed repair

IR:

ionizing radiation

NBS:

Nijmegen Breakage Syndrome

NHEJ:

non-homologous end joining

PARP-1:

poly ADP ribose polymerase-1

PIKK:

phosphatidylinositol 3-kinase-like protein kinase

PNKP:

polynucleotide kinase/phosphatase

RS-SCID:

Radiosensitive severe combined immunodeficiency

SNP:

single nucleotide polymorphism

ss:

single-stranded

SSB:

DNA single strand break

XLF:

XRCC4-like factor

References

  1. Abraham, R. T. 2004. PI 3-kinase related kinases: ‘big’ players in stress-induced signaling pathways. DNA Repair (Amst) 3:883–7.

    CAS  Google Scholar 

  2. Adimoolam, S., M. Sirisawad, J. Chen, P. Thiemann, J. M. Ford, and J. J. Buggy. 2007. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci USA 104:19482–7.

    PubMed  CAS  Google Scholar 

  3. Ahnesorg, P., P. Smith, and S. P. Jackson. 2006. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124:301–13.

    PubMed  CAS  Google Scholar 

  4. Aristegui, S. R., M. D. El-Murr, B. T. Golding, R. J. Griffin, and I. R. Hardcastle. 2006. Judicious application of allyl protecting groups for the synthesis of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors. Org Lett 8:5927–9.

    PubMed  CAS  Google Scholar 

  5. Audebert, M., B. Salles, and P. Calsou. 2004. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279:55117–26.

    PubMed  CAS  Google Scholar 

  6. Bao, S., Q. Wu, R. E. McLendon, Y. Hao, Q. Shi, A. B. Hjelmeland, M. W. Dewhirst, D. D. Bigner, and J. N. Rich. 2006. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–60.

    PubMed  CAS  Google Scholar 

  7. Barnes, D. E., G. Stamp, I. Rosewell, A. Denzel, and T. Lindahl. 1998. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr Biol 8:1395–8.

    PubMed  CAS  Google Scholar 

  8. Bassing, C. H., W. Swat, and F. W. Alt. 2002. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109 Suppl:S45–55.

    PubMed  Google Scholar 

  9. Baumann, M., W. Dubois, and H. D. Suit. 1990. Response of human squamous cell carcinoma xenografts of different sizes to irradiation: relationship of clonogenic cells, cellular radiation sensitivity in vivo, and tumor rescuing units. Radiat Res 123:325–30.

    PubMed  CAS  Google Scholar 

  10. Baumann, M., M. Krause, and R. Hill. 2008. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–54.

    PubMed  CAS  Google Scholar 

  11. Bennardo, N., A. Cheng, N. Huang, and J. M. Stark. 2008. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4:e1000110.

    PubMed  Google Scholar 

  12. Bennett, C. B., A. L. Lewis, K. K. Baldwin, and M. A. Resnick. 1993. Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proc Natl Acad Sci USA 90:5613–7.

    PubMed  CAS  Google Scholar 

  13. Bernstein, N. K., F. Karimi-Busheri, A. Rasouli-Nia, R. Mani, G. Dianov, J. N. Glover, and M. Weinfeld. 2008. Polynucleotide kinase as a potential target for enhancing cytotoxicity by ionizing radiation and topoisomerase I inhibitors. Anticancer Agents Med Chem 8:358–67.

    PubMed  CAS  Google Scholar 

  14. Bindra, R. S., P. J. Schaffer, A. Meng, J. Woo, K. Maseide, M. E. Roth, P. Lizardi, D. W. Hedley, R. G. Bristow, and P. M. Glazer. 2004. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 24:8504–18.

    PubMed  CAS  Google Scholar 

  15. Blazek, E. R., J. L. Foutch, and G. Maki. 2007. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5.

    PubMed  CAS  Google Scholar 

  16. Bleuyard, J. Y., M. E. Gallego, and C. I. White. 2006. Recent advances in understanding of the DNA double-strand break repair machinery of plants. DNA Repair (Amst) 5:1–12.

    CAS  Google Scholar 

  17. Blunt, T., N. J. Finnie, G. E. Taccioli, G. C. Smith, J. Demengeot, T. M. Gottlieb, R. Mizuta, A. J. Varghese, F. W. Alt, P. A. Jeggo, and et al. 1995. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell 80:813–23.

    PubMed  CAS  Google Scholar 

  18. Branzei, D., and M. Foiani. 2008. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9:297–308.

    PubMed  CAS  Google Scholar 

  19. Bryant, H. E., and T. Helleday. 2006. Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Nucleic Acids Res 34:1685–91.

    PubMed  CAS  Google Scholar 

  20. Bryant, H. E., N. Schultz, H. D. Thomas, K. M. Parker, D. Flower, E. Lopez, S. Kyle, M. Meuth, N. J. Curtin, and T. Helleday. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–7.

    PubMed  CAS  Google Scholar 

  21. Buck, D., L. Malivert, R. de Chasseval, A. Barraud, M. C. Fondaneche, O. Sanal, A. Plebani, J. L. Stephan, M. Hufnagel, F. le Deist, A. Fischer, A. Durandy, J. P. de Villartay, and P. Revy. 2006. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124:287–99.

    PubMed  CAS  Google Scholar 

  22. Buis, J., Y. Wu, Y. Deng, J. Leddon, G. Westfield, M. Eckersdorff, J. M. Sekiguchi, S. Chang, and D. O. Ferguson. 2008. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135:85–96.

    PubMed  CAS  Google Scholar 

  23. Chalmers, A. J. 2007. Radioresistant glioma stem cells–therapeutic obstacle or promising target? DNA Repair (Amst) 6:1391–4.

    CAS  Google Scholar 

  24. Chan, D. W., and S. P. Lees-Miller. 1996. The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit. J Biol Chem 271:8936–41.

    PubMed  CAS  Google Scholar 

  25. Chen, L., C. J. Nievera, A. Y. Lee, and X. Wu. 2008. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem 283:7713–20.

    PubMed  CAS  Google Scholar 

  26. Chen, X., S. Zhong, X. Zhu, B. Dziegielewska, T. Ellenberger, G. M. Wilson, A. D. MacKerell, Jr., and A. E. Tomkinson. 2008. Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair. Cancer Res 68:3169–77.

    PubMed  CAS  Google Scholar 

  27. Chernikova, S. B., R. L. Wells, and M. M. Elkind. 1999. Wortmannin sensitizes mammalian cells to radiation by inhibiting the DNA-dependent protein kinase-mediated rejoining of double-strand breaks. Radiat Res 151:159–66.

    PubMed  CAS  Google Scholar 

  28. Cimprich, K. A., and D. Cortez. 2008. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9:616–27.

    PubMed  CAS  Google Scholar 

  29. Collis, S. J., T. L. DeWeese, P. A. Jeggo, and A. R. Parker. 2005. The life and death of DNA-PK. Oncogene 24:949–61.

    PubMed  CAS  Google Scholar 

  30. D’Amours, D., and S. P. Jackson. 2002. The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–27.

    PubMed  Google Scholar 

  31. Damaraju, S., D. Murray, J. Dufour, D. Carandang, S. Myrehaug, G. Fallone, C. Field, R. Greiner, J. Hanson, C. E. Cass, and M. Parliament. 2006. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clin Cancer Res 12:2545–54.

    PubMed  CAS  Google Scholar 

  32. de Lange, T. 2005. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–10.

    PubMed  Google Scholar 

  33. Demuth, I., and M. Digweed. 2007. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome. Oncogene 26:7792–8.

    PubMed  CAS  Google Scholar 

  34. DiBiase, S. J., Z. C. Zeng, R. Chen, T. Hyslop, W. J. Curran, Jr., and G. Iliakis. 2000. DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 60:1245–53.

    PubMed  CAS  Google Scholar 

  35. Downs, J. A., and S. P. Jackson. 2004. A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5:367–78.

    PubMed  CAS  Google Scholar 

  36. Dudasova, Z., A. Dudas, and M. Chovanec. 2004. Non-homologous end-joining factors of Saccharomyces cerevisiae. FEMS Microbiol Rev 28:581–601.

    PubMed  CAS  Google Scholar 

  37. Dupre, A., L. Boyer-Chatenet, R. M. Sattler, A. P. Modi, J. H. Lee, M. L. Nicolette, L. Kopelovich, M. Jasin, R. Baer, T. T. Paull, and J. Gautier. 2008. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol 4:119–25.

    PubMed  CAS  Google Scholar 

  38. Durant, S., and P. Karran. 2003. Vanillins – a novel family of DNA-PK inhibitors. Nucleic Acids Res 31:5501–12.

    PubMed  CAS  Google Scholar 

  39. Edwards, S. L., R. Brough, C. J. Lord, R. Natrajan, R. Vatcheva, D. A. Levine, J. Boyd, J. S. Reis-Filho, and A. Ashworth. 2008. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–5.

    PubMed  CAS  Google Scholar 

  40. Evers, B., R. Drost, E. Schut, M. de Bruin, E. van der Burg, P. W. Derksen, H. Holstege, X. Liu, E. van Drunen, H. B. Beverloo, G. C. Smith, N. M. Martin, A. Lau, M. J. O’Connor, and J. Jonkers. 2008. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 14:3916–25.

    PubMed  CAS  Google Scholar 

  41. Farmer, H., N. McCabe, C. J. Lord, A. N. Tutt, D. A. Johnson, T. B. Richardson, M. Santarosa, K. J. Dillon, I. Hickson, C. Knights, N. M. Martin, S. P. Jackson, G. C. Smith, and A. Ashworth. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21.

    PubMed  CAS  Google Scholar 

  42. Fattah, K. R., B. L. Ruis, and E. A. Hendrickson. 2008. Mutations to Ku reveal differences in human somatic cell lines. DNA Repair (Amst) 7:762–74.

    CAS  Google Scholar 

  43. Frank, K. M., N. E. Sharpless, Y. Gao, J. M. Sekiguchi, D. O. Ferguson, C. Zhu, J. P. Manis, J. Horner, R. A. DePinho, and F. W. Alt. 2000. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 5:993–1002.

    PubMed  CAS  Google Scholar 

  44. Friedberg, E. C., G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz, and T. Ellenberger. 2005. DNA Repair and Mutagenesis, 2 ed. ASM Press, Washington, D.C.

    Google Scholar 

  45. Fu, Y. P., J. C. Yu, T. C. Cheng, M. A. Lou, G. C. Hsu, C. Y. Wu, S. T. Chen, H. S. Wu, P. E. Wu, and C. Y. Shen. 2003. Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63:2440–2446.

    PubMed  CAS  Google Scholar 

  46. Gaymes, T. J., S. Shall, F. Farzaneh, and G. J. Mufti. 2008. Chromosomal instability syndromes are sensitive to poly ADP ribose polymerase inhibitors. Haematologica.

    Google Scholar 

  47. Goodarzi, A. A., A. T. Noon, D. Deckbar, Y. Ziv, Y. Shiloh, M. Lobrich, and P. A. Jeggo. 2008. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 31:167–77.

    PubMed  CAS  Google Scholar 

  48. Griffin, R. J., G. Fontana, B. T. Golding, S. Guiard, I. R. Hardcastle, J. J. Leahy, N. Martin, C. Richardson, L. Rigoreau, M. Stockley, and G. C. Smith. 2005. Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro. J Med Chem 48:569–85.

    PubMed  CAS  Google Scholar 

  49. Gu, J., H. Lu, A. G. Tsai, K. Schwarz, and M. R. Lieber. 2007. Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. Nucleic Acids Res 35:5755–62.

    PubMed  CAS  Google Scholar 

  50. Gu, Y., S. Jin, Y. Gao, D. T. Weaver, and F. W. Alt. 1997. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc Natl Acad Sci USA 94:8076–81.

    PubMed  CAS  Google Scholar 

  51. Gu, Y., K. J. Seidl, G. A. Rathbun, C. Zhu, J. P. Manis, N. van der Stoep, L. Davidson, H. L. Cheng, J. M. Sekiguchi, K. Frank, P. Stanhope-Baker, M. S. Schlissel, D. B. Roth, and F. W. Alt. 1997. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7:653–65.

    PubMed  CAS  Google Scholar 

  52. Hall, E. J., and A. J. Giaccia. 2006. Radiobiology for the Radiobiologist, 6th ed. Lippincott Williams & Wilkins, Philadelphia.

    Google Scholar 

  53. Hardcastle, I. R., X. Cockcroft, N. J. Curtin, M. D. El-Murr, J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. Smith, and R. J. Griffin. 2005. Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach. J Med Chem 48:7829–7846.

    PubMed  CAS  Google Scholar 

  54. Harima, Y., S. Sawada, Y. Miyazaki, K. Kin, H. Ishihara, M. Imamura, M. Sougawa, N. Shikata, and T. Ohnishi. 2003. Expression of Ku80 in cervical cancer correlates with response to radiotherapy and survival. Am J Clin Oncol 26:e80–5.

    PubMed  Google Scholar 

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

    CAS  Google Scholar 

  56. Henning, W., and H. W. Sturzbecher. 2003. Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. Toxicology 193:91–109.

    PubMed  CAS  Google Scholar 

  57. Hickson, I., Y. Zhao, C. J. Richardson, S. J. Green, N. M. Martin, A. I. Orr, P. M. Reaper, S. P. Jackson, N. J. Curtin, and G. C. Smith. 2004. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64:9152–9.

    PubMed  CAS  Google Scholar 

  58. Hill, R. P., and L. Milas. 1989. The proportion of stem cells in murine tumors. Int J Radiat Oncol Biol Phys 16:513–8.

    PubMed  CAS  Google Scholar 

  59. Hoeijmakers, J. H. 2001. Genome maintenance mechanisms for preventing cancer. Nature 411:366–74.

    PubMed  CAS  Google Scholar 

  60. Hollick, J. J., L. J. Rigoreau, C. Cano-Soumillac, X. Cockcroft, N. J. Curtin, M. Frigerio, B. T. Golding, S. Guiard, I. R. Hardcastle, I. Hickson, M. G. Hummersone, K. A. Menear, N. M. Martin, I. Matthews, D. R. Newell, R. Ord, C. J. Richardson, G. C. Smith, and R. J. Griffin. 2007. Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. J Med Chem 50:1958–72.

    PubMed  CAS  Google Scholar 

  61. Howlett, N. G., T. Taniguchi, S. Olson, B. Cox, Q. Waisfisz, C. De Die-Smulders, N. Persky, M. Grompe, H. Joenje, G. Pals, H. Ikeda, E. A. Fox, and A. D. D’Andrea. 2002. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–9.

    PubMed  CAS  Google Scholar 

  62. Huertas, P., F. Cortes-Ledesma, A. A. Sartori, A. Aguilera, and S. P. Jackson. 2008. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455:689–92.

    PubMed  CAS  Google Scholar 

  63. Jankovic, M., A. Nussenzweig, and M. C. Nussenzweig. 2007. Antigen receptor diversification and chromosome translocations. Nat Immunol 8:801–8.

    PubMed  CAS  Google Scholar 

  64. Jazayeri, A., J. Falck, C. Lukas, J. Bartek, G. C. Smith, J. Lukas, and S. P. Jackson. 2006. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8:37–45.

    PubMed  CAS  Google Scholar 

  65. Jolly, C. J., A. J. Cook, and J. P. Manis. 2008. Fixing DNA breaks during class switch recombination. J Exp Med 205:509–13.

    PubMed  CAS  Google Scholar 

  66. Kaelin, W. G., Jr. 2005. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:689–98.

    PubMed  CAS  Google Scholar 

  67. Kastan, M. B., and J. Bartek. 2004. Cell-cycle checkpoints and cancer. Nature 432:316–23.

    PubMed  CAS  Google Scholar 

  68. Kienker, L. J., E. K. Shin, and K. Meek. 2000. Both V(D)J recombination and radioresistance require DNA-PK kinase activity, though minimal levels suffice for V(D)J recombination. Nucleic Acids Res 28:2752–61.

    PubMed  CAS  Google Scholar 

  69. Kim, J. S., T. B. Krasieva, H. Kurumizaka, D. J. Chen, A. M. Taylor, and K. Yokomori. 2005. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells. J Cell Biol 170:341–7.

    PubMed  CAS  Google Scholar 

  70. Kurimasa, A., S. Kumano, N. V. Boubnov, M. D. Story, C. S. Tung, S. R. Peterson, and D. J. Chen. 1999. Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining. Mol Cell Biol 19:3877–84.

    PubMed  CAS  Google Scholar 

  71. Kurz, E. U., and S. P. Lees-Miller. 2004. DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair (Amst) 3:889–900.

    CAS  Google Scholar 

  72. Lavin, M. F. 2008. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759–69.

    PubMed  CAS  Google Scholar 

  73. Lavin, M. F., and S. Kozlov. 2007. ATM activation and DNA damage response. Cell Cycle 6:931–42.

    PubMed  CAS  Google Scholar 

  74. Leahy, J. J., B. T. Golding, R. J. Griffin, I. R. Hardcastle, C. Richardson, L. Rigoreau, and G. C. Smith. 2004. Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg Med Chem Lett 14:6083–7.

    PubMed  CAS  Google Scholar 

  75. Lee, J. H., and T. T. Paull. 2007. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26:7741–8.

    PubMed  CAS  Google Scholar 

  76. Lee, S. W., K. J. Cho, J. H. Park, S. Y. Kim, S. Y. Nam, B. J. Lee, S. B. Kim, S. H. Choi, J. H. Kim, S. D. Ahn, S. S. Shin, E. K. Choi, and E. Yu. 2005. Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 62:1451–7.

    PubMed  CAS  Google Scholar 

  77. Lees-Miller, S. P., R. Godbout, D. W. Chan, M. Weinfeld, R. S. Day, 3rd, G. M. Barron, and J. Allalunis-Turner. 1995. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science 267:1183–5.

    PubMed  CAS  Google Scholar 

  78. Lengsfeld, B. M., A. J. Rattray, V. Bhaskara, R. Ghirlando, and T. T. Paull. 2007. Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol Cell 28:638–51.

    PubMed  CAS  Google Scholar 

  79. Li, S., N. S. Ting, L. Zheng, P. L. Chen, Y. Ziv, Y. Shiloh, E. Y. Lee, and W. H. Lee. 2000. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406:210–5.

    PubMed  CAS  Google Scholar 

  80. Li, X., and W. D. Heyer. 2008. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18:99–113.

    PubMed  CAS  Google Scholar 

  81. Lieber, M. R. 2008. The mechanism of human nonhomologous DNA end joining. J Biol Chem 283:1–5.

    PubMed  CAS  Google Scholar 

  82. Lieber, M. R., H. Lu, J. Gu, and K. Schwarz. 2008. Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining: relevance to cancer, aging, and the immune system. Cell Res 18:125–33.

    PubMed  CAS  Google Scholar 

  83. Limbo, O., C. Chahwan, Y. Yamada, R. A. de Bruin, C. Wittenberg, and P. Russell. 2007. Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol Cell 28:134–46.

    PubMed  CAS  Google Scholar 

  84. Liu, S. K., P. L. Olive, and R. G. Bristow. 2008. Biomarkers for DNA DSB inhibitors and radiotherapy clinical trials. Cancer Metastasis Rev 27:445–58.

    PubMed  CAS  Google Scholar 

  85. Lobrich, M., and P. A. Jeggo. 2007. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer 7:861–9.

    PubMed  Google Scholar 

  86. Longhese, M. P. 2008. DNA damage response at functional and dysfunctional telomeres. Genes Dev 22:125–40.

    PubMed  CAS  Google Scholar 

  87. Lord, C. J., and A. Ashworth. 2008. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 8(4):363–369.

    Google Scholar 

  88. Lu, H., U. Pannicke, K. Schwarz, and M. R. Lieber. 2007. Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J Biol Chem 282:11155–62.

    PubMed  CAS  Google Scholar 

  89. Ma, Y., U. Pannicke, K. Schwarz, and M. R. Lieber. 2002. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108:781–94.

    PubMed  CAS  Google Scholar 

  90. Ma, Y., K. Schwarz, and M. R. Lieber. 2005. The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst) 4:845–51.

    CAS  Google Scholar 

  91. Mahaney, B. L., K. Meek, and S. P. Lees Miller. 2009 Repair of ionizing radiation induced DNA double strand breaks by non-homologous end-joining. Biochem. J. 417:639–50.

    PubMed  CAS  Google Scholar 

  92. Manning, G., D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam. 2002. The protein kinase complement of the human genome. Science 298:1912–34.

    PubMed  CAS  Google Scholar 

  93. Martin, S. A., C. J. Lord, and A. Ashworth. 2008. DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev 18:80–6.

    PubMed  CAS  Google Scholar 

  94. McCabe, N., N. C. Turner, C. J. Lord, K. Kluzek, A. Bialkowska, S. Swift, S. Giavara, M. J. O’Connor, A. N. Tutt, M. Z. Zdzienicka, G. C. Smith, and A. Ashworth. 2006. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–15.

    PubMed  CAS  Google Scholar 

  95. Meek, K., V. Dang, and S. P. Lees Miller. 2008. DNA-PK: the means to justify the ends? Adv Immunol 99:33–58.

    PubMed  CAS  Google Scholar 

  96. Meek, K., P. Douglas, X. Cui, Q. Ding, and S. P. Lees-Miller. 2007. trans Autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining. Mol Cell Biol 27:3881–90.

    PubMed  CAS  Google Scholar 

  97. Meek, K., S. Gupta, D. A. Ramsden, and S. P. Lees-Miller. 2004. The DNA-dependent protein kinase: the director at the end. Immunol Rev 200:132–41.

    PubMed  CAS  Google Scholar 

  98. Menear, K. A., C. Adcock, R. Boulter, X. L. Cockcroft, L. Copsey, A. Cranston, K. J. Dillon, J. Drzewiecki, S. Garman, S. Gomez, H. Javaid, F. Kerrigan, C. Knights, A. Lau, V. M. Loh, Jr., I. T. Matthews, S. Moore, M. J. O’Connor, G. C. Smith, and N. M. Martin. 2008. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin- 1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51:6581–91.

    PubMed  CAS  Google Scholar 

  99. Mimitou, E. P., and L. S. Symington. 2008. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455:770–4.

    PubMed  CAS  Google Scholar 

  100. Miyagawa, K. 2008. Clinical relevance of the homologous recombination machinery in cancer therapy. Cancer Sci 99:187–94.

    PubMed  CAS  Google Scholar 

  101. Morrison, C., E. Sonoda, N. Takao, A. Shinohara, K. Yamamoto, and S. Takeda. 2000. The controlling role of ATM in homologous recombinational repair of DNA damage. Embo J 19:463–71.

    PubMed  CAS  Google Scholar 

  102. Moshous, D., I. Callebaut, R. de Chasseval, B. Corneo, M. Cavazzana-Calvo, F. Le Deist, I. Tezcan, O. Sanal, Y. Bertrand, N. Philippe, A. Fischer, and J. P. de Villartay. 2001. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105:177–86.

    PubMed  CAS  Google Scholar 

  103. Moshous, D., L. Li, R. Chasseval, N. Philippe, N. Jabado, M. J. Cowan, A. Fischer, and J. P. de Villartay. 2000. A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. Hum Mol Genet 9:583–8.

    PubMed  CAS  Google Scholar 

  104. Moynahan, M. E., T. Y. Cui, and M. Jasin. 2001. Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–50.

    PubMed  CAS  Google Scholar 

  105. Moynahan, M. E., A. J. Pierce, and M. Jasin. 2001. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7:263–72.

    PubMed  CAS  Google Scholar 

  106. Nussenzweig, A., C. Chen, V. da Costa Soares, M. Sanchez, K. Sokol, M. C. Nussenzweig, and G. C. Li. 1996. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382:551–5.

    PubMed  CAS  Google Scholar 

  107. Nussenzweig, A., and M. C. Nussenzweig. 2007. A backup DNA repair pathway moves to the forefront. Cell 131:223–5.

    PubMed  CAS  Google Scholar 

  108. O’Connor, M. J., N. M. Martin, and G. C. Smith. 2007. Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene 26:7816–24.

    PubMed  Google Scholar 

  109. O’Driscoll, M., K. M. Cerosaletti, P. M. Girard, Y. Dai, M. Stumm, B. Kysela, B. Hirsch, A. Gennery, S. E. Palmer, J. Seidel, R. A. Gatti, R. Varon, M. A. Oettinger, H. Neitzel, P. A. Jeggo, and P. Concannon. 2001. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8:1175–85.

    PubMed  Google Scholar 

  110. O’Driscoll, M., A. R. Gennery, J. Seidel, P. Concannon, and P. A. Jeggo. 2004. An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair (Amst) 3:1227–35.

    Google Scholar 

  111. O’Driscoll, M., and P. A. Jeggo. 2006. The role of double-strand break repair – insights from human genetics. Nat Rev Genet 7:45–54.

    PubMed  Google Scholar 

  112. O’Driscoll, M., V. L. Ruiz-Perez, C. G. Woods, P. A. Jeggo, and J. A. Goodship. 2003. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497–501.

    PubMed  Google Scholar 

  113. Pastwa, E., and M. Malinowski. 2007. Non-homologous DNA end joining in anticancer therapy. Curr Cancer Drug Targets 7:243–50.

    PubMed  CAS  Google Scholar 

  114. Phillips, T. M., W. H. McBride, and F. Pajonk. 2006. The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–85.

    PubMed  Google Scholar 

  115. Povirk, L. F. 2006. Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. DNA Repair (Amst) 5:1199–212.

    CAS  Google Scholar 

  116. Povirk, L. F., T. Zhou, R. Zhou, M. J. Cowan, and S. M. Yannone. 2007. Processing of 3’-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease. J Biol Chem 282:3547–58.

    PubMed  CAS  Google Scholar 

  117. Powell, S. N., and L. A. Kachnic. 2008. Therapeutic exploitation of tumor cell defects in homologous recombination. Anticancer Agents Med Chem 8:448–60.

    PubMed  CAS  Google Scholar 

  118. Rainey, M. D., M. E. Charlton, R. V. Stanton, and M. B. Kastan. 2008. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res 68:7466–74.

    PubMed  CAS  Google Scholar 

  119. Raji, H., and E. Hartsuiker. 2006. Double-strand break repair and homologous recombination in Schizosaccharomyces pombe. Yeast 23:963–76.

    PubMed  CAS  Google Scholar 

  120. Revy, P., L. Malivert, and J. P. de Villartay. 2006. Cernunnos-XLF, a recently identified non-homologous end-joining factor required for the development of the immune system. Curr Opin Allergy Clin Immunol 6:416–20.

    PubMed  CAS  Google Scholar 

  121. Riballo, E., M. Kuhne, N. Rief, A. Doherty, G. C. Smith, M. J. Recio, C. Reis, K. Dahm, A. Fricke, A. Krempler, A. R. Parker, S. P. Jackson, A. Gennery, P. A. Jeggo, and M. Lobrich. 2004. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16:715–24.

    PubMed  CAS  Google Scholar 

  122. Rosenzweig, K. E., M. B. Youmell, S. T. Palayoor, and B. D. Price. 1997. Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin Cancer Res 3:1149–56.

    PubMed  CAS  Google Scholar 

  123. Rothkamm, K., I. Kruger, L. H. Thompson, and M. Lobrich. 2003. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23:5706–15.

    PubMed  CAS  Google Scholar 

  124. Rottenberg, S., J. E. Jaspers, A. Kersbergen, E. van der Burg, A. O. Nygren, S. A. Zander, P. W. Derksen, M. de Bruin, J. Zevenhoven, A. Lau, R. Boulter, A. Cranston, M. J. O’Connor, N. M. Martin, P. Borst, and J. Jonkers. 2008. 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.

    PubMed  CAS  Google Scholar 

  125. Saar, K., K. H. Chrzanowska, M. Stumm, M. Jung, G. Nurnberg, T. F. Wienker, E. Seemanova, R. D. Wegner, A. Reis, and K. Sperling. 1997. The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet 60:605–10.

    PubMed  CAS  Google Scholar 

  126. San Filippo, J., P. Sung, and H. Klein. 2008. Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 77:229–57.

    PubMed  CAS  Google Scholar 

  127. Sartori, A. A., C. Lukas, J. Coates, M. Mistrik, S. Fu, J. Bartek, R. Baer, J. Lukas, and S. P. Jackson. 2007. Human CtIP promotes DNA end resection. Nature 450:509–14.

    PubMed  CAS  Google Scholar 

  128. Savitsky, K., A. Bar-Shira, S. Gilad, G. Rotman, Y. Ziv, L. Vanagaite, D. A. Tagle, S. Smith, T. Uziel, S. Sfez, and et al. 1995. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–53.

    PubMed  CAS  Google Scholar 

  129. Schreiber, V., F. Dantzer, J. C. Ame, and G. de Murcia. 2006. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–28.

    PubMed  CAS  Google Scholar 

  130. Shiloh, Y. 2006. The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31:402–410.

    PubMed  CAS  Google Scholar 

  131. Shinohara, E. T., L. Geng, J. Tan, H. Chen, Y. Shir, E. Edwards, J. Halbrook, E. A. Kesicki, A. Kashishian, and D. E. Hallahan. 2005. DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs. Cancer Res 65:4987–92.

    PubMed  CAS  Google Scholar 

  132. Shrivastav, M., L. P. De Haro, and J. A. Nickoloff. 2008. Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134–47.

    PubMed  CAS  Google Scholar 

  133. Shuman, S., and M. S. Glickman. 2007. Bacterial DNA repair by non-homologous end joining. Nat Rev Microbiol 5:852–61.

    PubMed  CAS  Google Scholar 

  134. Snouwaert, J. N., L. C. Gowen, A. M. Latour, A. R. Mohn, A. Xiao, L. DiBiase, and B. H. Koller. 1999. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. Oncogene 18:7900–7.

    PubMed  CAS  Google Scholar 

  135. Stavnezer, J., J. E. Guikema, and C. E. Schrader. 2008. Mechanism and regulation of class switch recombination. Annu Rev Immunol 26:261–92.

    PubMed  CAS  Google Scholar 

  136. Stewart, G. S., R. S. Maser, T. Stankovic, D. A. Bressan, M. I. Kaplan, N. G. Jaspers, A. Raams, P. J. Byrd, J. H. Petrini, and A. M. Taylor. 1999. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:577–87.

    PubMed  CAS  Google Scholar 

  137. Sung, P., and H. Klein. 2006. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7:739–50.

    PubMed  CAS  Google Scholar 

  138. Takeda, S., K. Nakamura, Y. Taniguchi, and T. T. Paull. 2007. Ctp1/CtIP and the MRN complex collaborate in the initial steps of homologous recombination. Mol Cell 28:351–2.

    PubMed  CAS  Google Scholar 

  139. Uematsu, N., E. Weterings, K. Yano, K. Morotomi-Yano, B. Jakob, G. Taucher-Scholz, P. O. Mari, D. C. van Gent, B. P. Chen, and D. J. Chen. 2007. Autophosphorylation of DNA-PKcs regulates its dynamics at DNA double-strand breaks. J Cell Biol 177:219–29.

    PubMed  CAS  Google Scholar 

  140. van der Burg, M., H. Ijspeert, N. S. Verkaik, T. Turul, W. W. Wiegant, K. Morotomi-Yano, P. O. Mari, I. Tezcan, D. J. Chen, M. Z. Zdzienicka, J. J. van Dongen, and D. C. van Gent. 2009. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest 119:91–8.

    PubMed  Google Scholar 

  141. Wang, H., B. Rosidi, R. Perrault, M. Wang, L. Zhang, F. Windhofer, and G. Iliakis. 2005. DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65:4020–30.

    PubMed  CAS  Google Scholar 

  142. Wang, M., W. Wu, B. Rosidi, L. Zhang, H. Wang, and G. Iliakis. 2006. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34:6170–82.

    PubMed  CAS  Google Scholar 

  143. Wang, X., and A. D. D’Andrea. 2004. The interplay of Fanconi anemia proteins in the DNA damage response. DNA Repair (Amst) 3:1063–9.

    CAS  Google Scholar 

  144. West, S. C. 2003. Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4:435–45.

    PubMed  CAS  Google Scholar 

  145. Weterings, E., and D. J. Chen. 2007. DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys? J Cell Biol 179:183–6.

    PubMed  CAS  Google Scholar 

  146. Weterings, E., and D. J. Chen. 2008. The endless tale of non-homologous end-joining. Cell Res 18:114–24.

    PubMed  CAS  Google Scholar 

  147. Willems, P., K. Claes, A. Baeyens, V. Vandersickel, J. Werbrouck, K. De Ruyck, B. Poppe, R. Van den Broecke, A. Makar, E. Marras, G. Perletti, H. Thierens, and A. Vral. 2008. Polymorphisms in nonhomologous end-joining genes associated with breast cancer risk and chromosomal radiosensitivity. Genes Chromosomes Cancer 47:137–48.

    PubMed  CAS  Google Scholar 

  148. Williams, R. S., G. Moncalian, J. S. Williams, Y. Yamada, O. Limbo, D. S. Shin, L. M. Groocock, D. Cahill, C. Hitomi, G. Guenther, D. Moiani, J. P. Carney, P. Russell, and J. A. Tainer. 2008. Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135:97–109.

    PubMed  CAS  Google Scholar 

  149. Williams, R. S., J. S. Williams, and J. A. Tainer. 2007. Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol 85:509–20.

    PubMed  CAS  Google Scholar 

  150. Willmore, E., S. L. Elliott, T. Mainou-Fowler, G. P. Summerfield, G. H. Jackson, F. O’Neill, C. Lowe, A. Carter, R. Harris, A. R. Pettitt, C. Cano-Soumillac, R. J. Griffin, I. G. Cowell, C. A. Austin, and B. W. Durkacz. 2008. DNA-dependent protein kinase is a therapeutic target and an indicator of poor prognosis in B-cell chronic lymphocytic leukemia. Clin Cancer Res 14:3984–92.

    PubMed  CAS  Google Scholar 

  151. Wilson, C. R., S. E. Davidson, G. P. Margison, S. P. Jackson, J. H. Hendry, and C. M. West. 2000. Expression of Ku70 correlates with survival in carcinoma of the cervix. Br J Cancer 83:1702–6.

    PubMed  CAS  Google Scholar 

  152. Yan, C. T., C. Boboila, E. K. Souza, S. Franco, T. R. Hickernell, M. Murphy, S. Gumaste, M. Geyer, A. A. Zarrin, J. P. Manis, K. Rajewsky, and F. W. Alt. 2007. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449:478–482.

    PubMed  CAS  Google Scholar 

  153. Yano, K., K. Morotomi-Yano, S. Y. Wang, N. Uematsu, K. J. Lee, A. Asaithamby, E. Weterings, and D. J. Chen. 2008. Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9:91–6.

    PubMed  CAS  Google Scholar 

  154. Yu, X., and J. Chen. 2004. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol 24:9478–86.

    PubMed  CAS  Google Scholar 

  155. Yu, X., S. Fu, M. Lai, R. Baer, and J. Chen. 2006. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20:1721–6.

    PubMed  CAS  Google Scholar 

  156. Zhao, Y., H. D. Thomas, M. A. Batey, I. G. Cowell, C. J. Richardson, R. J. Griffin, A. H. Calvert, D. R. Newell, G. C. Smith, and N. J. Curtin. 2006. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 66:5354–62.

    PubMed  CAS  Google Scholar 

  157. Zhu, Z., W. H. Chung, E. Y. Shim, S. E. Lee, and G. Ira. 2008. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134:981–94.

    PubMed  CAS  Google Scholar 

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Acknowledgements

Thanks to Drs E. Kurz, T. Beattie, J. Cobb and G. Bebb for helpful comments. LMW and CTW are supported by graduate studentships from the Alberta Heritage Foundation for Medical Research (AHFMR) (LMW) and Alberta Health Services (LMW and CTW). SPLM is a scientist of the AHFMR and holds the Engineered Air Chair in Cancer Research.

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  1. Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, University of Calgary, 3330 Hospital Drive NW, T2N 4N1, Calgary, AB, Canada

    Laura M. Williamson, Chris T. Williamson & Susan P. Lees-Miller

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  1. Signal Transduction Laboratory, Queensland Institute of Medical Research, Herston Road 300, Herston, 4006, Australia

    Kum Kum Khanna

  2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Yosef Shiloh

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Williamson, L.M., Williamson, C.T., Lees-Miller, S.P. (2009). DNA Double Strand Break Repair: Mechanisms and Therapeutic Potential. In: Khanna, K., Shiloh, Y. (eds) The DNA Damage Response: Implications on Cancer Formation and Treatment. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2561-6_8

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