Skip to main content
SpringerLink
Log in

DNA-PK, a Pharmacological Target in Cancer Chemotherapy and Radiotherapy?

  • Chapter
  • First Online:
Advances in DNA Repair in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 72))

  • 1259 Accesses

Abstract

In the search for ways of sensitizing tumor cells to chemotherapy or radiotherapy, the inhibition of DNA repair has recently been proposed as a target of clinical interest. Ionizing radiations, as well as several antitumor drugs, induce the formation of DNA double-strand breaks (DSBs), that are highly damaging to the DNA, leading to cell death and genomic instability. DSBs are mainly repaired by the Nonhomologous End joining (NHEJ) process, in which DNA dependent protein kinase (DNA-PK) is the key complex. Consequently, specific DNA-PK inhibitors have been selected and evaluated for sensitizing cells to chemotherapy or radiotherapy. The choice of DNA-PK as a pharmacological target of interest in cancer treatment is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jeggo PA, Lobrich M (2007) DNA double-strand breaks: their cellular and clinical impact? Oncogene 26(56):7717–7719

    Article  PubMed  CAS  Google Scholar 

  2. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078

    Article  PubMed  CAS  Google Scholar 

  3. Kastan MB (2008) DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture. Mol Cancer Res 6(4):517–524

    Article  PubMed  CAS  Google Scholar 

  4. Lobrich M, Jeggo PA (2007) The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer 7(11):861–869

    Article  PubMed  CAS  Google Scholar 

  5. Jeggo P, Lavin MF (2009) Cellular radiosensitivity: how much better do we understand it? Int J Radiat Biol 85(12):1061–1081

    Article  PubMed  CAS  Google Scholar 

  6. O’Driscoll M, Jeggo PA (2006) The role of double-strand break repair—insights from human genetics. Nat Rev Genet 7(1):45–54

    Article  PubMed  CAS  Google Scholar 

  7. Begg AC, Stewart FA, Vens C (2011) Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 11(4):239–253

    Article  PubMed  CAS  Google Scholar 

  8. Helleday T, Petermann E, Lundin C et al (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8(3):193–204

    Article  PubMed  CAS  Google Scholar 

  9. Guzi TJ, Paruch K, Dwyer MP et al (2011) Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther 10(4):591–602

    Article  PubMed  CAS  Google Scholar 

  10. McNeely S, Conti C, Sheikh T et al (2010) Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase. Cell Cycle 9(5):995–1004

    Article  PubMed  CAS  Google Scholar 

  11. Morgan MA, Parsels LA, Zhao L et al (2010) Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res 70(12):4972–4981

    Article  PubMed  CAS  Google Scholar 

  12. Walton MI, Eve PD, Hayes A et al (2010) The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106. Mol Cancer Ther 9(1):89–100

    Article  PubMed  CAS  Google Scholar 

  13. Ouyang H, Nussenzweig A, Kurimasa A et al (1997) Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J Exp Med 186(6):921–929

    Article  PubMed  CAS  Google Scholar 

  14. Lees-Miller SP, Godbout R, Chan DW et al (1995) Absence of p350 subunit of DNA activated protein kinase from a radiosensitive human cell line. Science 267(5201):1183–1185

    Article  PubMed  CAS  Google Scholar 

  15. Burma S, Chen BP, Chen DJ (2006) Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst) 5(9–10):1042–1048

    Article  CAS  Google Scholar 

  16. Goodhead DT (1994) Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 65(1):7–17

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Blaisdell JO, Harrison L, Wallace SS (2001) Base excision repair processing of radiation induced clustered DNA lesions. Radiat Prot Dosimetry 97(1):25–31

    Article  PubMed  CAS  Google Scholar 

  19. Asaithamby A, Hu B, Chen DJ (2011) Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci U S A 108(20):8293–8298

    Article  PubMed  CAS  Google Scholar 

  20. Sedelnikova OA, Redon CE, Dickey JS et al (2010) Role of oxidatively induced DNA lesions in human pathogenesis. Mutat Res 704(1–3):152–159

    PubMed  CAS  Google Scholar 

  21. Singleton BK, Griffin CS, Thacker J (2002) Clustered DNA damage leads to complex genetic changes in irradiated human cells. Cancer Res 62(21):6263–6269

    PubMed  CAS  Google Scholar 

  22. Pommier Y, Leo E, Zhang H et al (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17(5):421–433

    Article  PubMed  CAS  Google Scholar 

  23. Strumberg D, Pilon AA, Smith M et al (2000) Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol Cell Biol 20(11):3977–3987

    Article  PubMed  CAS  Google Scholar 

  24. Akkari YM, Bateman RL, Reifsteck CA et al (2000) DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand cross-links. Mol Cell Biol 20(21):8283–8289

    Article  PubMed  CAS  Google Scholar 

  25. De Silva IU, McHugh PJ, Clingen PH et al (2000) Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol Cell Biol 20(21):7980–7990

    Article  PubMed  Google Scholar 

  26. Raschle M, Knipscheer P, Enoiu M et al (2008) Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134(6):969–980

    Article  PubMed  CAS  Google Scholar 

  27. Kennedy DR, Gawron LS, Ju J et al (2007) Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks. Cancer Res 67(2):773–781

    Article  PubMed  CAS  Google Scholar 

  28. Povirk LF (1996) DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: bleomycin, neocarzinostatin and other enediynes. Mutat Res 355(1–2):71–89

    PubMed  Google Scholar 

  29. Sutherland BM, Bennett PV, Sidorkina O et al (2000) Clustered damages and total lesions induced in DNA by ionizing radiation: oxidized bases and strand breaks. Biochemistry 39(27):8026–8031

    Article  PubMed  CAS  Google Scholar 

  30. Van Lanen SG, Shen B (2008) Biosynthesis of enediyne antitumor antibiotics. Curr Top Med Chem 8(6):448–459

    Article  PubMed  Google Scholar 

  31. Xu YJ, Zhen YS, Goldberg IH (1994) C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage. Biochemistry 33(19):5947–5954

    Article  PubMed  CAS  Google Scholar 

  32. Elmroth K, Nygren J, Martensson S et al (2003) Cleavage of cellular DNA by calicheamicin gamma1. DNA Repair (Amst) 2(4):363–374

    Article  CAS  Google Scholar 

  33. Mao Z, Bozzella M, Seluanov A et al (2008) DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle 7(18):2902–2906

    Article  PubMed  CAS  Google Scholar 

  34. Shrivastav M, De Haro LP, Nickoloff JA (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res 18(1):134–147

    Article  PubMed  CAS  Google Scholar 

  35. Neal JA, Dang V, Douglas P et al (2011) Inhibition of homologous recombination by DNA-dependent protein kinase requires kinase activity, is titratable, and is modulated by autophosphorylation. Mol Cell Biol 31(8):1719–1733

    Article  PubMed  CAS  Google Scholar 

  36. Bonner WM, Redon CE, Dickey JS et al (2008) GammaH2AX and cancer. Nat Rev Cancer 8(12):957–967

    Article  PubMed  CAS  Google Scholar 

  37. Lord CJ, Ashworth A (2009) Bringing DNA repair in tumors into focus. Clin Cancer Res 15(10):3241–3243

    Article  PubMed  CAS  Google Scholar 

  38. Banuelos CA, Banath JP, Kim JY et al (2009) gammaH2AX expression in tumors exposed to cisplatin and fractionated irradiation. Clin Cancer Res 15(10):3344–3353

    Article  PubMed  CAS  Google Scholar 

  39. Rogakou EP, Pilch DR, Orr AH et al (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868

    Article  PubMed  CAS  Google Scholar 

  40. Soutoglou E, Misteli T (2008) Activation of the cellular DNA damage response in the absence of DNA lesions. Science 320(5882):1507–1510

    Article  PubMed  CAS  Google Scholar 

  41. Misteli T, Soutoglou E (2009) The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat Rev Mol Cell Biol 10(4):243–254

    Article  PubMed  CAS  Google Scholar 

  42. Pospelova TV, Demidenko ZN, Bukreeva EI et al (2009) Pseudo-DNA damage response in senescent cells. Cell Cycle 8(24):4112–4118

    Article  PubMed  CAS  Google Scholar 

  43. Toledo LI, Murga M, Gutierrez-Martinez P et al (2008) ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev 22(3):297–302

    Article  PubMed  CAS  Google Scholar 

  44. Bouquet F, Ousset M, Biard D et al (2011) A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia. J Cell Sci 124(Pt 11):1943–1951

    Article  PubMed  CAS  Google Scholar 

  45. Wyman C, Kanaar R (2006) DNA double-strand break repair: all’s well that ends well. Annu Rev Genet 40:363–383

    Article  PubMed  CAS  Google Scholar 

  46. Pardo B, Gomez-Gonzalez B, Aguilera A (2009) DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci 66(6):1039–1056

    Article  PubMed  CAS  Google Scholar 

  47. Ma JL, Kim EM, Haber JE et al (2003) Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol Cell Biol 23(23):8820–8828

    Article  PubMed  CAS  Google Scholar 

  48. Wang H, Perrault AR, Takeda Y et al (2003) Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res 31(18):5377–5388

    Article  PubMed  CAS  Google Scholar 

  49. Nussenzweig A, Nussenzweig MC (2007) A backup DNA repair pathway moves to the forefront. Cell 131(2):223–225

    Article  PubMed  CAS  Google Scholar 

  50. Soulas-Sprauel P, Rivera-Munoz P, Malivert L et al (2007) V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining. Oncogene 26(56):7780–7791

    Article  PubMed  CAS  Google Scholar 

  51. Weterings E, Chen DJ (2008) The endless tale of non-homologous end-joining. Cell Res 18(1):114–124

    Article  PubMed  CAS  Google Scholar 

  52. Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211

    Article  PubMed  CAS  Google Scholar 

  53. Downs JA, Jackson SP (2004) A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5(5):367–378

    Article  PubMed  CAS  Google Scholar 

  54. Yano K, Morotomi-Yano K, Wang SY et al (2008) Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9(1):91–96

    Article  PubMed  CAS  Google Scholar 

  55. Wu PY, Frit P, Meesala S et al (2009) Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol Cell Biol 29(11):3163–3172

    Article  PubMed  CAS  Google Scholar 

  56. Drouet J, Delteil C, Lefrancois J et al (2005) DNA-dependent protein kinase and XRCC4- DNA ligase IV mobilization in the cell in response to DNA double strand breaks. J Biol Chem 280(8):7060–7069

    Article  PubMed  CAS  Google Scholar 

  57. Drouet J, Frit P, Delteil C et al (2006) Interplay between Ku, Artemis, and the DNA dependent protein kinase catalytic subunit at DNA ends. J Biol Chem 281(38):27784–27793

    Article  PubMed  CAS  Google Scholar 

  58. Wu PY, Frit P, Malivert L et al (2007) Interplay between Cernunnos-XLF and nonhomologous end-joining proteins at DNA ends in the cell. J Biol Chem 282(44):31937–31943

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Goodarzi AA, Yu Y, Riballo E et al (2006) DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J 25(16):3880–3889

    Article  PubMed  CAS  Google Scholar 

  61. Riballo E, Woodbine L, Stiff T et al (2009) XLF-Cernunnos promotes DNA ligase IV-XRCC4 re-adenylation following ligation. Nucleic Acids Res 37(2):482–492

    Article  PubMed  CAS  Google Scholar 

  62. Budman J, Kim SA, Chu G (2007) Processing of DNA for nonhomologous end-joining is controlled by kinase activity and XRCC4/ligase IV. J Biol Chem 282(16):11950–11959

    Article  PubMed  CAS  Google Scholar 

  63. Akopiants K, Zhou RZ, Mohapatra S et al (2009) Requirement for XLF/Cernunnos in alignment-based gap filling by DNA polymerases lambda and mu for nonhomologous end joining in human whole-cell extracts. Nucleic Acids Res 37(12):4055–4062

    Article  PubMed  CAS  Google Scholar 

  64. Haber JE (2008) Alternative endings. Proc Natl Acad Sci U S A 105(2):405–406

    Article  PubMed  CAS  Google Scholar 

  65. McVey M, Lee SE (2008) MMEJ repair of double-strand breaks (director’s cut): deleted sequences and alternative endings. Trends Genet 24(11):529–538

    Article  PubMed  CAS  Google Scholar 

  66. Maser RS, Wong KK, Sahin E et al (2007) DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol Cell Biol 27(6):2253–2265

    Article  PubMed  CAS  Google Scholar 

  67. Bombarde O, Boby C, Gomez D et al (2010) TRF2/RAP1 and DNA-PK mediate a double protection against joining at telomeric ends. EMBO J 29(9):1573–1584

    Article  PubMed  CAS  Google Scholar 

  68. Riha K, Heacock ML, Shippen DE (2006) The role of the nonhomologous end-joining DNA double-strand break repair pathway in telomere biology. Annu Rev Genet 40:237–277

    Article  PubMed  CAS  Google Scholar 

  69. Wang M, Wu W, Rosidi B et al (2006) PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34(21):6170–6182

    Article  PubMed  CAS  Google Scholar 

  70. Liang L, Deng L, Chen Y et al (2005) Modulation of DNA end joining by nuclear proteins. J Biol Chem 280(36):31442–31449

    Article  PubMed  CAS  Google Scholar 

  71. Audebert M, Salles B, Calsou P (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(53):55117–55126

    Article  PubMed  CAS  Google Scholar 

  72. Audebert M, Salles B, Weinfeld M et al (2006) Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway. J Mol Biol 356(2):257–265

    Article  PubMed  CAS  Google Scholar 

  73. Wang H, Rosidi B, Perrault R et al (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65(10):4020–4030

    Article  PubMed  CAS  Google Scholar 

  74. Audebert M, Salles B, Calsou P (2008) Effect of double-strand break DNA sequence on the PARP-1 NHEJ pathway. Biochem Biophys Res Commun 369(3):982–988

    Article  PubMed  CAS  Google Scholar 

  75. Deng Y, Guo X, Ferguson DO et al (2009) Multiple roles for MRE11 at uncapped telomeres. Nature 460(7257):914–918

    Article  PubMed  CAS  Google Scholar 

  76. Deriano L, Stracker TH, Baker A et al (2009) Roles for NBS1 in alternative nonhomologous end-joining of V(D)J recombination intermediates. Mol Cell 34(1):13–25

    Article  PubMed  CAS  Google Scholar 

  77. Dinkelmann M, Spehalski E, Stoneham T et al (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol 16(8):808–813

    Article  PubMed  CAS  Google Scholar 

  78. Rass E, Grabarz A, Plo I et al (2009) Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 16(8):819–824

    Article  PubMed  CAS  Google Scholar 

  79. Xie A, Kwok A, Scully R (2009) Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16(8):814–818

    Article  PubMed  CAS  Google Scholar 

  80. Zhuang J, Jiang G, Willers H et al (2009) Exonuclease function of human Mre11 promotes deletional nonhomologous end joining. J Biol Chem 284(44):30565–30573

    Article  PubMed  CAS  Google Scholar 

  81. Cheng Q, Barboule N, Frit P et al (2011) Ku counteracts mobilization of PARP1 and MRN in chromatin damaged with DNA double-strand breaks. Nucleic Acids Res 39:9605–9619

    Article  PubMed  CAS  Google Scholar 

  82. Singh SK, Wu W, Zhang L et al (2011) Widespread dependence of backup NHEJ on growth state: ramifications for the use of DNA-PK inhibitors. Int J Radiat Oncol Biol Phys 79(2):540–548

    Article  PubMed  CAS  Google Scholar 

  83. Wu W, Wang M, Singh SK et al (2008) Repair of radiation induced DNA double strand breaks by backup NHEJ is enhanced in G2. DNA Repair (Amst) 7(2):329–338

    Article  CAS  Google Scholar 

  84. Weinstock DM, Brunet EJasin M (2007) Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nat Cell Biol 9(8):978–981

    Article  PubMed  CAS  Google Scholar 

  85. Fattah F, Lee EH, Weisensel N et al (2010) Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. PLoS Genet 6(2):e1000855

    Article  PubMed  CAS  Google Scholar 

  86. Boboila C, Yan C, Wesemann DR et al (2010) Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med 207(2):417–427

    Article  PubMed  CAS  Google Scholar 

  87. Mansour WY, Schumacher S, Rosskopf R et al (2008) Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks. Nucleic Acids Res 36(12):4088–4098

    Article  PubMed  CAS  Google Scholar 

  88. Guirouilh-Barbat J, Rass E, Plo I et al (2007) Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends. Proc Natl Acad Sci U S A 104(52):20902–20907

    Article  PubMed  CAS  Google Scholar 

  89. Schulte-Uentrop L, El-Awady RA, Schliecker L et al (2008) Distinct roles of XRCC4 and Ku80 in non-homologous end-joining of endonuclease- and ionizing radiation-induced DNA double-strand breaks. Nucleic Acids Res 36(8):2561–2569

    Article  PubMed  CAS  Google Scholar 

  90. Kuhfittig-Kulle S, Feldmann E, Odersky A et al (2007) The mutagenic potential of nonhomologous end joining in the absence of the NHEJ core factors Ku70/80, DNA-PKcs and XRCC4-LigIV. Mutagenesis 22(3):217–233

    Article  PubMed  CAS  Google Scholar 

  91. Guirouilh-Barbat J, Huck S, Bertrand P et al (2004) Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells. Mol Cell 14(5):611–623

    Article  PubMed  CAS  Google Scholar 

  92. Corneo B, Wendland RL, Deriano L et al (2007) Rag mutations reveal robust alternative end joining. Nature 449(7161):483–486

    Article  PubMed  CAS  Google Scholar 

  93. Yan CT, Boboila C, Souza EK et al (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449(7161):478–482

    Article  PubMed  CAS  Google Scholar 

  94. Mansour WY, Rhein T, Dahm-Daphi J (2010) The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Res 38(18):6065–6077

    Article  PubMed  CAS  Google Scholar 

  95. Rooney S, Chaudhuri J, Alt FW (2004) The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev 200:115–131

    Article  PubMed  CAS  Google Scholar 

  96. Boboila C, Jankovic M, Yan CT et al (2010) Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A 107(7):3034–3039

    Article  PubMed  CAS  Google Scholar 

  97. Simsek D, Jasin M (2010) Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nat Struct Mol Biol 17(4):410–416

    Article  PubMed  CAS  Google Scholar 

  98. Walker JR, Corpina RA, Goldberg J (2001) Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412(6847):607–614

    Article  PubMed  CAS  Google Scholar 

  99. Zhang Z, Hu W, Cano L et al (2004) Solution structure of the C-terminal domain of Ku80 suggests important sites for protein-protein interactions. Structure 12(3):495–502

    Article  PubMed  CAS  Google Scholar 

  100. Harris R, Esposito D, Sankar A et al (2004) The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR). J Mol Biol 335(2):573–582

    Article  PubMed  CAS  Google Scholar 

  101. Rivera-Calzada A, Spagnolo L, Pearl LH et al (2007) Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs. EMBO Rep 8(1):56–62

    Article  PubMed  CAS  Google Scholar 

  102. DeFazio LG, Stansel RM, Griffith JD et al (2002) Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J 21(12):3192–3200

    Article  PubMed  CAS  Google Scholar 

  103. Hammarsten O, Chu G (1998) DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proc Natl Acad Sci U S A 95(2):525–530

    Article  PubMed  CAS  Google Scholar 

  104. Lees-Miller SP, Sakaguchi K, Ullrich SJ et al (1992) Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. Mol Cell Biol 12(11):5041–5049

    PubMed  CAS  Google Scholar 

  105. Niewolik D, Pannicke U, Lu H et al (2006) DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5′ or 3′ overhangs. J Biol Chem 281(45):33900–33909

    Article  PubMed  CAS  Google Scholar 

  106. Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31(7):402–410

    Article  PubMed  CAS  Google Scholar 

  107. Lavin MF, Kozlov S (2007) ATM activation and DNA damage response. Cell Cycle 6(8):931–942

    Article  PubMed  CAS  Google Scholar 

  108. Chan DW, Lees-Miller SP (1996) The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit. J Biol Chem 271(15):8936–8941

    Article  PubMed  CAS  Google Scholar 

  109. Meek K, Douglas P, Cui X et al (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(10):3881–3890

    Article  PubMed  CAS  Google Scholar 

  110. Douglas P, Sapkota GP, Morrice N et al (2002) Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. Biochem J 368(Pt 1):243–251

    Article  PubMed  CAS  Google Scholar 

  111. Cui X, Yu Y, Gupta S et al (2005) Autophosphorylation of DNA-dependent protein kinase regulates DNA end processing and may also alter double-strand break repair pathway choice. Mol Cell Biol 25(24):10842–10852

    Article  PubMed  CAS  Google Scholar 

  112. Chen BP, Chan DW, Kobayashi J et al (2005) Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J Biol Chem 280(15):14709–14715

    Article  PubMed  CAS  Google Scholar 

  113. Douglas P, Cui X, Block WD et al (2007) The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol 27(5):1581–1591

    Article  PubMed  CAS  Google Scholar 

  114. Hammel M, Yu Y, Mahaney BL et al (2010) Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. J Biol Chem 285(2):1414–1423

    Article  PubMed  CAS  Google Scholar 

  115. Merkle D, Douglas P, Moorhead GB et al (2002) The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. Biochemistry 41(42):12706–12714

    Article  PubMed  CAS  Google Scholar 

  116. Uematsu N, Weterings E, Yano K et al (2007) Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J Cell Biol 177(2):219–229

    Article  PubMed  CAS  Google Scholar 

  117. Chiu CY, Cary RB, Chen DJ et al (1998) Cryo-EM imaging of the catalytic subunit of the DNA-dependent protein kinase. J Mol Biol 284(4):1075–1081

    Article  PubMed  CAS  Google Scholar 

  118. Leuther KK, Hammarsten O, Kornberg RD et al (1999) Structure of DNA-dependent protein kinase: implications for its regulation by DNA. EMBO J 18(5):1114–1123

    Article  PubMed  CAS  Google Scholar 

  119. Rivera-Calzada A, Maman JD, Spagnolo L et al (2005) Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Structure 13(2):243–255

    Article  PubMed  CAS  Google Scholar 

  120. Williams DR, Lee KJ, Shi J et al (2008) Cryo-EM structure of the DNA-dependent protein kinase catalytic subunit at subnanometer resolution reveals alpha helices and insight into DNA binding. Structure 16(3):468–477

    Article  PubMed  CAS  Google Scholar 

  121. Sibanda BL, Chirgadze DY, Blundell TL (2010) Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature 463(7277):118–121

    Article  PubMed  CAS  Google Scholar 

  122. Ochi T, Sibanda BL, Wu Q et al (2010) Structural biology of DNA repair: spatial organisation of the multicomponent complexes of nonhomologous end joining. J Nucleic Acids pii:621695

    Google Scholar 

  123. Dobbs TA, Tainer JA, Lees-Miller SP (2010) A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair (Amst) 9(12):1307–1314

    Article  CAS  Google Scholar 

  124. Morris EP, Rivera-Calzada A, da Fonseca PC et al (2011) Evidence for a remodelling of DNAPK upon autophosphorylation from electron microscopy studies. Nucleic Acids Res 39(13):5757–5767

    Article  PubMed  CAS  Google Scholar 

  125. Moorhead GB, Trinkle-Mulcahy L, Ulke-Lemee A (2007) Emerging roles of nuclear protein phosphatases. Nat Rev Mol Cell Biol 8(3):234–244

    Article  PubMed  CAS  Google Scholar 

  126. Douglas P, Moorhead GBG, Ye R et al (2001) Protein phosphatases regulate DNA-dependent protein kinase activity. J Biol Chem 276(22):18992–18998

    Article  PubMed  CAS  Google Scholar 

  127. Nakada S, Chen GI, Gingras AC et al (2008) PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint. EMBO Rep 9(10):1019–1026

    Article  PubMed  CAS  Google Scholar 

  128. Wang B, Zhao A, Sun L et al (2008) Protein phosphatase PP4 is overexpressed in human breast and lung tumors. Cell Res 18(9):974–977

    Article  PubMed  CAS  Google Scholar 

  129. Chowdhury D, Xu X, Zhong X et al (2008) A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication. Mol Cell 31(1):33–46

    Article  PubMed  CAS  Google Scholar 

  130. Keogh MC, Kim JA, Downey M et al (2006) A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery. Nature 439(7075):497–501

    Article  PubMed  CAS  Google Scholar 

  131. Douglas P, Zhong J, Ye R et al (2010) Protein phosphatase 6 interacts with the DNA-dependent protein kinase catalytic subunit and dephosphorylates gamma-H2AX. Mol Cell Biol 30(6):1368–1381

    Article  PubMed  CAS  Google Scholar 

  132. O’Connor MJ, Martin NM, Smith GC (2007) Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene 26(56):7816–7824

    Article  PubMed  CAS  Google Scholar 

  133. Shinohara ET, Geng L, Tan J et al (2005) DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs. Cancer Res 65(12):4987–4992

    Article  PubMed  CAS  Google Scholar 

  134. Muller C, Dusseau C, Calsou P et al (1998) Human normal peripheral blood B-lymphocytes are deficient in DNA-dependent protein kinase activity due to the expression of a variant form of the Ku86 protein. Oncogene 16(12):1553–1560

    Article  PubMed  CAS  Google Scholar 

  135. Muller C, Christodoulopoulos G, Salles B et al (1998) DNA-Dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood 92(7):2213–2219

    PubMed  CAS  Google Scholar 

  136. Muller C, Calsou P, Salles B (2000) The activity of the DNA-dependent protein kinase (DNAPK) complex is determinant in the cellular response to nitrogen mustards. Biochimie 82(1):25–28

    Article  PubMed  CAS  Google Scholar 

  137. Christodoulopoulos G, Muller C, Salles B et al (1998) Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic leukemia by inhibition of DNA-dependent protein kinase activity using wortmannin. Cancer Res 58(9):1789–1792

    PubMed  CAS  Google Scholar 

  138. Weidhaas JB, Babar I, Nallur SM et al (2007) MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 67(23):11111–11116

    Article  PubMed  CAS  Google Scholar 

  139. Windhofer F, Wu W, Iliakis G (2007) Low levels of DNA ligases III and IV sufficient for effective NHEJ. J Cell Physiol 213(2):475–483

    Article  PubMed  CAS  Google Scholar 

  140. Yan D, Ng WL, Zhang X et al (2010) Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One 5(7):e11397

    Article  PubMed  CAS  Google Scholar 

  141. Takeda AA, de Barros AC, Chang CW et al (2011) Structural basis of importin-alpha-mediated nuclear transport for Ku70 and Ku80. J Mol Biol 412(2):226–234

    Article  PubMed  CAS  Google Scholar 

  142. Ohno M, Kunimoto M, Nishizuka M et al (2009) Ku proteins function as corepressors to regulate farnesoid X receptor-mediated gene expression. Biochem Biophys Res Commun 390(3):738–742

    Article  PubMed  CAS  Google Scholar 

  143. Kim E, Li K, Lieu C et al (2008) Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. J Hepatol 49(5):787–798

    Article  PubMed  CAS  Google Scholar 

  144. Bednarek R, Boncela J, Smolarczyk K et al (2008) Ku80 as a novel receptor for thymosin beta4 that mediates its intracellular activity different from G-actin sequestering. J Biol Chem 283(3):1534–1544

    Article  PubMed  CAS  Google Scholar 

  145. Shi L, Qiu D, Zhao G et al (2007) Dynamic binding of Ku80, Ku70 and NF90 to the IL-2 promoter in vivo in activated T-cells. Nucleic Acids Res 35(7):2302–2310

    Article  PubMed  CAS  Google Scholar 

  146. Munakata Y, Saito-Ito T, Kumura-Ishii K et al (2005) Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection. Blood 106(10):3449–3456

    Article  PubMed  CAS  Google Scholar 

  147. Muller C, Paupert J, Monferran S et al (2005) The double life of the Ku protein: facing the DNA breaks and the extracellular environment. Cell Cycle 4(3):438–441

    Article  PubMed  CAS  Google Scholar 

  148. Monferran S, Paupert J, Dauvillier S et al (2004) The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase 9. EMBO J 23(19):3758–3768

    Article  PubMed  CAS  Google Scholar 

  149. Quanz M, Berthault N, Roulin C et al (2009) Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy. Clin Cancer Res 15(4):1308–1316

    Article  PubMed  CAS  Google Scholar 

  150. Quanz M, Chassoux D, Berthault N et al (2009) Hyperactivation of DNA-PK by doublestrand break mimicking molecules disorganizes DNA damage response. PLoS One 4(7):e6298

    Article  PubMed  CAS  Google Scholar 

  151. Berthault N, Maury B, Agrario C et al (2011) Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems. Cancer Gene Ther 18:695–706

    Article  PubMed  CAS  Google Scholar 

  152. Rosenzweig KE, Youmell MB, Palayoor ST et al (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(7):1149–1156

    PubMed  CAS  Google Scholar 

  153. Veuger SJ, Curtin NJ, Richardson CJ et al (2003) Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res 63(18):6008–6015

    PubMed  CAS  Google Scholar 

  154. Amrein L, Loignon M, Goulet AC et al (2007) Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase. J Pharmacol Exp Ther 321(3):848–855

    Article  PubMed  CAS  Google Scholar 

  155. Zhao Y, Thomas HD, Batey MA et al (2006) Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 66(10):5354–5362

    Article  PubMed  CAS  Google Scholar 

  156. Willmore E, Elliott SL, Mainou-Fowler T et al (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(12):3984–3992

    Article  PubMed  CAS  Google Scholar 

  157. Elliott SL, Crawford C, Mulligan E et al (2011) Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia. Br J Haematol 152(1):61–71

    Article  PubMed  CAS  Google Scholar 

  158. Davidson D, Coulombe Y, Martinez-Marignac VL et al (2011) Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells. Invest New Drugs 30:1248–1256

    Article  PubMed  CAS  Google Scholar 

  159. Martin SA, Lord CJ, Ashworth A (2008) DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev 18(1):80–86

    Article  PubMed  CAS  Google Scholar 

  160. Li S, Takeda Y, Wragg S et al (2003) Modification of the ionizing radiation response in living cells by an scFv against the DNA-dependent protein kinase. Nucleic Acids Res 31(20):5848–5857

    Article  PubMed  CAS  Google Scholar 

  161. Du L, Zhou LJ, Pan XJ et al (2010) Radiosensitization and growth inhibition of cancer cells mediated by an scFv antibody gene against DNA-PKcs in vitro and in vivo. Radiat Oncol 5:70

    Article  PubMed  CAS  Google Scholar 

  162. Moeller BJ, Sidman RL, Pasqualini R et al (2011) Discovery of DNA repair inhibitors by combinatorial library profiling. Cancer Res 71(5):1816–1824

    Article  PubMed  CAS  Google Scholar 

  163. Shang ZF, Huang B, Xu QZ et al (2010) Inactivation of DNA-dependent protein kinase leads to spindle disruption and mitotic catastrophe with attenuated checkpoint protein 2 phosphorylation in response to DNA damage. Cancer Res 70(9):3657–3666

    Article  PubMed  CAS  Google Scholar 

  164. Wong RH, Chang I, Hudak CS et al (2009) A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136(6):1056–1072

    Article  PubMed  CAS  Google Scholar 

  165. Britton S, Froment C, Frit P et al (2009) Cell nonhomologous end joining capacity controls SAF-A phosphorylation by DNA-PK in response to DNA double-strand breaks inducers. Cell Cycle 8(22):3717–3722

    Article  PubMed  CAS  Google Scholar 

  166. Shi M, Vivian CJ, Lee KJ et al (2009) DNA-PKcs-PIDDosome: a nuclear caspase-2-activating complex with role in G2/M checkpoint maintenance. Cell 136(3):508–520

    Article  PubMed  CAS  Google Scholar 

  167. Johnson AB, Denko NBarton MC (2008) Hypoxia induces a novel signature of chromatin modifications and global repression of transcription. Mutat Res 640(1–2):174–179

    PubMed  CAS  Google Scholar 

  168. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  PubMed  CAS  Google Scholar 

  169. Kong X, Shen Y, Jiang N et al (2011) Emerging roles of DNA-PK besides DNA repair. Cell Signal 23:1273–1280

    Article  PubMed  CAS  Google Scholar 

  170. Soderlund Leifler K, Queseth S, Fornander T et al (2010) Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer. Int J Oncol 37(6):1547–1554

    PubMed  Google Scholar 

  171. Beskow C, Skikuniene J, Holgersson A et al (2009) Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86. Br J Cancer 101(5):816–821

    Article  PubMed  CAS  Google Scholar 

  172. Hosoi Y, Watanabe T, Nakagawa K et al (2004) Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol 25(2):461–468

    PubMed  CAS  Google Scholar 

  173. Ader I, Muller C, Bonnet J et al (2002) The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit. Oncogene 21(42):6471–6479

    Article  PubMed  CAS  Google Scholar 

  174. Tonotsuka N, Hosoi Y, Miyazaki S et al (2006) Heterogeneous expression of DNA-dependent protein kinase in esophageal cancer and normal epithelium. Int J Mol Med 18(3):441–447

    PubMed  CAS  Google Scholar 

  175. Shintani S, Mihara M, Li C et al (2003) Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma. Cancer Sci 94(10):894–900

    Article  PubMed  CAS  Google Scholar 

  176. Deriano L, Guipaud O, Merle-Beral H et al (2005) Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway. Blood 105(12):4776–4783

    Article  PubMed  CAS  Google Scholar 

  177. Miquel C, Jacob S, Grandjouan S et al (2007) Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability. Oncogene 26(40):5919–5926

    Article  PubMed  CAS  Google Scholar 

  178. Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917

    Article  PubMed  CAS  Google Scholar 

  179. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921

    Article  PubMed  CAS  Google Scholar 

  180. Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134

    Article  PubMed  CAS  Google Scholar 

  181. Fong PC, Yap TA, Boss DS et al (2010) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28(15):2512–2519

    Article  PubMed  CAS  Google Scholar 

  182. Carden CP, Yap TA, Kaye SB (2010) PARP inhibition: targeting the Achilles’ heel of DNA repair to treat germline and sporadic ovarian cancers. Curr Opin Oncol 22(5):473–480

    Article  PubMed  CAS  Google Scholar 

  183. Patel AG, Sarkaria JN, Kaufmann SH (2011) Nonhomologous end joining drives poly(ADPribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 108(8):3406–3411

    Article  PubMed  CAS  Google Scholar 

  184. Helleday T (2010) Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis 31(6):955–960

    Article  PubMed  CAS  Google Scholar 

  185. Chan N, Pires IM, Bencokova Z et al (2010) Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 70(20):8045–8054

    Article  PubMed  CAS  Google Scholar 

  186. Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5:387–393

    Article  PubMed  CAS  Google Scholar 

  187. Bolderson E, Richard DJ, Zhou BB et al (2009) Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin Cancer Res 15(20):6314–6320

    Article  PubMed  CAS  Google Scholar 

  188. Yap TA, Sandhu SK, Carden CP et al (2011) Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin 61(1):31–49

    Article  PubMed  Google Scholar 

  189. Fauman EB, Rai BK, Huang ES (2011) Structure-based druggability assessment-identifying suitable targets for small molecule therapeutics. Curr Opin Chem Biol 15(4):463–468

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work from the team “Radiobiology and DNA repair” at CNRS IPBS has been supported by grants from Ligue nationale contre le cancer (équipe labelisée), Electricité de France (EDF), Institut National du Cancer (INCA), and Cancéropole Grand-Sud Ouest. Bernard Salles and Gladys Mirey are Professor and Associate Professor, respectively, at Faculty of Pharmacy, and Patrick Calsou is a scientist from INSERM.

Author information

Authors and Affiliations

  1. INRA, UMR1331, Toxalim (Research Centre in Food Toxicology), Université de Toulouse III, 180 chemin de Tournefeuille, Toulouse, F-31027, France

    Bernard Salles D.V.M., Ph.D. & Gladys Mirey Ph.D.

  2. CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, Toulouse, F-31077, France

    Patrick Calsou M.D., Ph.D.

Authors
  1. Bernard Salles D.V.M., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Calsou M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gladys Mirey Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernard Salles D.V.M., Ph.D. .

Editor information

Editors and Affiliations

  1. Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, Canada

    Lawrence Panasci

  2. , Department of Oncology, McGill University, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Raquel Aloyz

  3. McGill University, Department of Medicine and Oncology, Faculty of Medicine, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Moulay Alaoui-Jamali

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Salles, B., Calsou, P., Mirey, G. (2013). DNA-PK, a Pharmacological Target in Cancer Chemotherapy and Radiotherapy?. In: Panasci, L., Aloyz, R., Alaoui-Jamali, M. (eds) Advances in DNA Repair in Cancer Therapy. Cancer Drug Discovery and Development, vol 72. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4741-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-4741-2_2

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-4740-5

  • Online ISBN: 978-1-4614-4741-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation