Molecular pathways involved in cell death after chemically induced DNA damage

  • Roberto Sánchez-Olea
  • Mónica R. Calera
  • Alexei Degterev
Part of the Experientia Supplementum book series (EXS, volume 99)


DNA damage is at the center of the genesis, progression and treatment of cancer. We review here the molecular mechanisms of the DNA damage inducing small molecules most commonly used in cancer therapy. Cell cycle control and DNA repair mechanisms are known to be activated after DNA damage. Here, we revise recent discoveries related to the cell cycle control and DNA repair processes and how these findings are being utilized for the more efficient, powerful and selective therapies for cancer treatment.


PARP Inhibitor Homologous Recombination Pathway PARP Inhibitor AG14361 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wall ME, Wani MC (1995) Camptothecin and taxol: Discovery to Res 55: 753–760Google Scholar
  2. 2.
    Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260: 14873–14878PubMedGoogle Scholar
  3. 3.
    Eng WK, Faucette L, Johnson RK, Sternglanz R (1988) Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 34: 755–760PubMedGoogle Scholar
  4. 4.
    Nitiss J, Wang JC (1988) DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci USA 85: 7501–7505PubMedCrossRefGoogle Scholar
  5. 5.
    Stewart L, Redinbo MR, Qiu X, Hol WG, Champoux JJ (1998) A model for the mechanism of human topoisomerase I. Science 279: 1534–1541PubMedCrossRefGoogle Scholar
  6. 6.
    Holm C, Covey JM, Kerrigan D, Pommier Y (1989) Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49: 6365–6368PubMedGoogle Scholar
  7. 7.
    Horwitz SB, Horwitz MS (1973) Effects of camptothecin on the breakage and repair of DNA durMolecular pathways involved in cell death after chemically induced DNA damage 225 ing the cell cycle. Cancer Res 33: 2834–2836PubMedGoogle Scholar
  8. 8.
    O’Connor PM, Nieves-Neira W, Kerrigan D, Bertrand R, Goldman J, Kohn KW, Pommier Y (1991) S-phase population analysis does not correlate with the cytotoxicity of camptothecin and 10,11-methylenedioxycamptothecin in human colon carcinoma HT-29 cells. Cancer Commun 3: 233–240PubMedGoogle Scholar
  9. 9.
    Hsiang YH, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49: 5077–5082PubMedGoogle Scholar
  10. 10.
    Wu J, Liu LF (1997) Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res 25: 4181–4186PubMedCrossRefGoogle Scholar
  11. 11.
    Morris EJ, Geller HM (1996) Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: Evidence for cell cycle-independent toxicity. J Cell Biol 134: 757–770PubMedCrossRefGoogle Scholar
  12. 12.
    Borovitskaya AE, D’Arpa P (1998) Replication-dependent and-independent camptothecin cytotoxicity of seven human colon tumor cell lines. Oncol Res 10: 271–276PubMedGoogle Scholar
  13. 13.
    Pommier Y, Weinstein JN, Aladjem MI, Kohn KW (2006) Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clin Cancer Res 12: 2657–2661PubMedCrossRefGoogle Scholar
  14. 14.
    Shiloh Y, Lehmann AR (2004) Maintaining integrity. Nat Cell Biol 6: 923–928PubMedCrossRefGoogle Scholar
  15. 15.
    Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432: 316–323PubMedCrossRefGoogle Scholar
  16. 16.
    Takemura H, Rao VA, Sordet O, Furuta T, Miao ZH, Meng L, Zhang H, Pommier Y (2006) Defective Mre11-dependent activation of Chk2 by Ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem 281: 30814–30823PubMedCrossRefGoogle Scholar
  17. 17.
    Smith PJ, Makinson TA, Watson JV (1989) Enhanced sensitivity to camptothecin in Ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I. Int J Radiat Biol 55: 217–231PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson MA, Bryant PE, Jones NJ (2000) Isolation of camptothecin-sensitive chinese hamster cell mutants: Phenotypic heterogeneity within the Ataxia telangiectasia-like XRCC8 (irs2) complementation group. Mutagenesis 15: 367–374PubMedCrossRefGoogle Scholar
  19. 19.
    Flatten K, Dai NT, Vroman BT, Loegering D, Erlichman C, Karnitz LM, Kaufmann SH (2005) The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. J Biol Chem 280: 14349–14355PubMedCrossRefGoogle Scholar
  20. 20.
    Yu Q, Rose JH, Zhang H, Pommier Y (2001) Antisense inhibition of Chk2/hCds1 expression attenuates DNA damage-induced S and G2 checkpoints and enhances apoptotic activity in HEK-293 cells. FEBS Lett 505: 7–12PubMedCrossRefGoogle Scholar
  21. 21.
    Gupta M, Fan S, Zhan Q, Kohn KW, O’Connor PM, Pommier Y (1997) Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. Clin Cancer Res 3: 1653–1660PubMedGoogle Scholar
  22. 22.
    Han Z, Wei W, Dunaway S, Darnowski JW, Calabresi P, Sedivy J, Hendrickson EA, Balan KV, Pantazis P, Wyche JH (2002) Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J Biol Chem 277: 17154–17160PubMedCrossRefGoogle Scholar
  23. 23.
    Squires S, Ryan AJ, Strutt HL, Johnson RT (1993) Hypersensitivity of Cockayne’s syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Cancer Res 53: 2012–2019PubMedGoogle Scholar
  24. 24.
    Chen AY, Liu LF (1994) DNA topoisomerases: Essential enzymes and lethal targets. Annu Rev Pharmacol Toxicol 34: 191–218PubMedCrossRefGoogle Scholar
  25. 25.
    Liu LF (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58: 351–375PubMedCrossRefGoogle Scholar
  26. 26.
    Nitiss JL, Wang JC (1996) Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol Pharmacol 50: 1095–1102PubMedGoogle Scholar
  27. 27.
    Tsai-Pflugfelder M, Liu LF, Liu AA, Tewey KM, Whang-Peng J, Knutsen T, Huebner K, Croce CM, Wang JC (1988) Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22. Proc Natl Acad Sci USA 85: 7177–7181PubMedCrossRefGoogle Scholar
  28. 28.
    Treszezamsky AD, Kachnic LA, Feng Z, Zhang J, Tokadjian C, Powell SN (2007) BRCA1-and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer Res 67: 7078–7081PubMedCrossRefGoogle Scholar
  29. 29.
    Wong E, Giandomenico CM (1999) Current status of platinum-based antitumor drugs. Chem Rev 99: 2451–2466Google Scholar
  30. 30.
    Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. 226 R. Sánchez-Olea et al. Chem Rev 99: 2467–2498PubMedCrossRefGoogle Scholar
  31. 31.
    Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4: 307–320PubMedCrossRefGoogle Scholar
  32. 32.
    Kartalou M, Essigmann JM (2001) Recognition of cisplatin adducts by cellular proteins. Mutat Res 478: 1–21PubMedGoogle Scholar
  33. 33.
    Harrap KR (1985) Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Treat Rev 12 Suppl A: 21–33PubMedCrossRefGoogle Scholar
  34. 34.
    Raynaud FI, Boxall FE, Goddard PM, Valenti M, Jones M, Murrer BA, Abrams M, Kelland LR (1997) Cis-Amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: In vivo activity, toxicology, and pharmacokinetics in mice. Clin Cancer Res 3: 2063–2074PubMedGoogle Scholar
  35. 35.
    Holford J, Sharp SY, Murrer BA, Abrams M, Kelland LR (1998) In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473. Br J Cancer 77: 366–373PubMedGoogle Scholar
  36. 36.
    Ishida S, Lee J, Thiele DJ, Herskowitz I (2002) Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA 99: 14298–14302PubMedCrossRefGoogle Scholar
  37. 37.
    Holzer AK, Samimi G, Katano K, Naerdemann W, Lin X, Safaei R, Howell SB (2004) The copper influx transporter human copper transport protein 1 regulates the uptake of cisplatin in human ovarian carcinoma cells. Mol Pharmacol 66: 817–823PubMedCrossRefGoogle Scholar
  38. 38.
    Komatsu M, Sumizawa T, Mutoh M, Chen ZS, Terada K, Furukawa T,Yang XL, Gao H, Miura N, Sugiyama T, Akiyama S (2000) Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res 60: 1312–1316PubMedGoogle Scholar
  39. 39.
    Miyashita H, Nitta Y, Mori S, Kanzaki A, Nakayama K, Terada K, Sugiyama T, Kawamura H, Sato A, Morikawa H et al (2003) Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin. Oral Oncol 39: 157–162PubMedCrossRefGoogle Scholar
  40. 40.
    Nakayama K, Kanzaki A, Ogawa K, Miyazaki K, Neamati N, Takebayashi Y (2002) Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: Comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP. Int J Cancer 101: 488–495PubMedCrossRefGoogle Scholar
  41. 41.
    Ohbu M, Ogawa K, Konno S, Kanzaki A, Terada K, Sugiyama T, Takebayashi Y (2003) Coppertransporting P-type adenosine triphosphatase (ATP7B) is expressed in human gastric carcinoma. Cancer Lett 189: 33–38PubMedCrossRefGoogle Scholar
  42. 42.
    Cui Y, Konig J, Buchholz JK, Spring H, Leier I, Keppler D (1999) Drug resistance and ATPdependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55: 929–937PubMedGoogle Scholar
  43. 43.
    Kool M, de Haas M, Scheffer GL, Scheper RJ, van Eijk MJ, Juijn JA, Baas F, Borst P (1997) Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 57: 3537–3547PubMedGoogle Scholar
  44. 44.
    Koike K, Kawabe T, Tanaka T, Toh S, Uchiumi T,Wada M, Akiyama S, Ono M, Kuwano M (1997) A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res 57: 5475–5479PubMedGoogle Scholar
  45. 45.
    Corda Y, Job C, Anin MF, Leng M, Job D (1991) Transcription by eucaryotic and procaryotic RNA polymerases of DNA modified at a d(GG) or a d(AG) site by the antitumor drug cisdiamminedichloroplatinum( II). Biochemistry 30: 222–230PubMedCrossRefGoogle Scholar
  46. 46.
    Corda Y, Job C, Anin MF, Leng M, Job D (1993) Spectrum of DNA-platinum adduct recognition by prokaryotic and eukaryotic DNA-dependent RNA polymerases. Biochemistry 32: 8582–8588PubMedCrossRefGoogle Scholar
  47. 47.
    Tornaletti S, Patrick SM, Turchi JJ, Hanawalt PC (2003) Behavior of T7 RNA polymerase and mammalian RNA polymerase II at site-specific cisplatin adducts in the template DNA. J Biol Chem 278: 35791–35797PubMedCrossRefGoogle Scholar
  48. 48.
    Jung Y, Lippard SJ (2006) RNA polymerase II blockage by cisplatin-damaged DNA. Stability and polyubiquitylation of stalled polymerase. J Biol Chem 281: 1361–1370PubMedCrossRefGoogle Scholar
  49. 49.
    Damsma GE, Alt A, Brueckner F, Carell T, Cramer P (2007) Mechanism of transcriptional stalling at cisplatin-damaged DNA. Nat Struct Mol Biol 14: 1127–1133PubMedCrossRefGoogle Scholar
  50. 50.
    Zamble DB, Mikata Y, Eng CH, Sandman KE, Lippard SJ (2002) Testis-specific HMG-domain protein alters the responses of cells to cisplatin. J Inorg Biochem 91: 451–462PubMedCrossRefGoogle Scholar
  51. 51.
    Huang JC, Zamble DB, Reardon JT, Lippard SJ, Sancar A (1994) HMG-domain proteins specifiMolecular pathways involved in cell death after chemically induced DNA damage 227 cally inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc Natl Acad Sci USA 91: 10394–10398PubMedCrossRefGoogle Scholar
  52. 52.
    He Q, Liang CH, Lippard SJ (2000) Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin. Proc Natl Acad Sci USA 97: 5768–5772PubMedCrossRefGoogle Scholar
  53. 53.
    Bruhn SL, Pil PM, Essigmann JM, Housman DE, Lippard SJ (1992) Isolation and characterization of human cDNA clones encoding a high mobility group box protein that recognizes structural distortions to DNA caused by binding of the anticancer agent cisplatin. Proc Natl Acad Sci USA 89: 2307–2311Google Scholar
  54. 54.
    Yarnell AT, Oh S, Reinberg D, Lippard SJ (2001) Interaction of FACT, SSRP1, and the high mobility group (HMG) domain of SSRP1 with DNA damaged by the anticancer drug cisplatin. J Biol Chem 276: 25736–25741PubMedCrossRefGoogle Scholar
  55. 55.
    Shaul Y (2000) C-Abl: Activation and nuclear targets. Cell Death Differ 7: 10–16PubMedCrossRefGoogle Scholar
  56. 56.
    Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, Wang JY (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399: 806–809PubMedCrossRefGoogle Scholar
  57. 57.
    Machuy N, Rajalingam K, Rudel T (2004) Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis. Cell Death Differ 11: 290–300PubMedCrossRefGoogle Scholar
  58. 58.
    Kharbanda S, Pandey P,Yamauchi T, Kumar S, Kaneki M, Kumar V, Bharti A,Yuan ZM, Ghanem L, Rana A et al (2000) Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage. Mol Cell Biol 20: 4979–4989PubMedCrossRefGoogle Scholar
  59. 59.
    Pandey P, Raingeaud J, Kaneki M, Weichselbaum R, Davis RJ, Kufe D, Kharbanda S (1996) Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and-independent mechanisms. J Biol Chem 271: 23775–23779PubMedCrossRefGoogle Scholar
  60. 60.
    Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, Sadler PJ, Jodrell DI (2002) In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer. Br J Cancer 86: 1652–1657PubMedCrossRefGoogle Scholar
  61. 61.
    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) From bench to bedside-Preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J Inorg Biochem 100: 891–904PubMedCrossRefGoogle Scholar
  62. 62.
    Bergamo A, Sava G (2007) Ruthenium complexes can target determinants of tumour malignancy. Dalton Trans 13: 1267–1272PubMedCrossRefGoogle Scholar
  63. 63.
    d’Adda di Fagagna F, Hande MP, Tong WM, Lansdorp PM, Wang ZQ, Jackson SP (1999) Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nat Genet 23: 76–80Google Scholar
  64. 64.
    Jagtap P, Szabo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4: 421–440PubMedCrossRefGoogle Scholar
  65. 65.
    Dantzer F, Schreiber V, Niedergang C, Trucco C, Flatter E, De La Rubia G, Oliver J, Rolli V, Menissier-de Murcia J, de Murcia G (1999) Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81: 69–75PubMedCrossRefGoogle Scholar
  66. 66.
    Boulton S, Kyle S, Durkacz BW (1999) Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. Carcinogenesis 20: 199–203PubMedCrossRefGoogle Scholar
  67. 67.
    El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW (2003) A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 31: 5526–5533Google Scholar
  68. 68.
    D’silva I, Pelletier JD, Lagueux J, D’Amours D, Chaudhry MA, Weinfeld M, Lees-Miller SP, Poirier GG (1999) Relative affinities of poly(ADP-ribose) polymerase and DNA-dependent protein kinase for DNA strand interruptions. Biochim Biophys Acta 1430: 119–126Google Scholar
  69. 69.
    Noel G, Giocanti N, Fernet M, Megnin-Chanet F, Favaudon V (2003) Poly(ADP-ribose) polymerase (PARP-1) is not involved in DNA double-strand break recovery. BMC Cell Biol 4: 7–17PubMedCrossRefGoogle Scholar
  70. 70.
    Yang YG, Cortes U, Patnaik S, Jasin M, Wang ZQ (2004) 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: 3872–3882PubMedCrossRefGoogle Scholar
  71. 71.
    de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M et al (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94: 7303–7307PubMedCrossRefGoogle Scholar
  72. 72.
    Wang ZQ, Stingl L, Morrison C, Jantsch M, Los M, Schulze-Osthoff K, Wagner EF (1997) PARP 228 R. Sanchez-Olea et al. is important for genomic stability but dispensable in apoptosis. Genes Dev 11: 2347–2358PubMedCrossRefGoogle Scholar
  73. 73.
    Conde C, Mark M, Oliver FJ, Huber A, de Murcia G, Menissier-de Murcia J (2001) Loss of poly(ADP-ribose) polymerase-1 causes increased tumour latency in p53-deficient mice. EMBO J 20: 3535–3543Google Scholar
  74. 74.
    Schultz N, Lopez E, Saleh-Gohari N, Helleday T (2003) Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res 31: 4959–4964PubMedCrossRefGoogle Scholar
  75. 75.
    Arnaudeau C, Lundin C, Helleday T (2001) 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: 1235–1245PubMedCrossRefGoogle Scholar
  76. 76.
    Haber JE (1999) DNA recombination: The replication connection. Trends Biochem Sci 24: 271–275PubMedCrossRefGoogle Scholar
  77. 77.
    Symington LS (2005) Focus on recombinational DNA repair. EMBO Rep 6: 512–517PubMedCrossRefGoogle Scholar
  78. 78.
    Tutt A, Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8: 571–576PubMedCrossRefGoogle Scholar
  79. 79.
    Moynahan ME, Pierce AJ, Jasin M (2001) BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7: 263–272PubMedCrossRefGoogle Scholar
  80. 80.
    Moynahan ME, Chiu JW, Koller BH, Jasin M (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4: 511–518PubMedCrossRefGoogle Scholar
  81. 81.
    Davies OR, Pellegrini L (2007) Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nat Struct Mol Biol 14: 475–483PubMedGoogle Scholar
  82. 82.
    Esashi F, Galkin VE, Yu X, Egelman EH, West SC (2007) Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat Struct Mol Biol 14: 468–474PubMedCrossRefGoogle Scholar
  83. 83.
    Gudmundsdottir K, Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25: 5864–5874PubMedCrossRefGoogle Scholar
  84. 84.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADPribose) polymerase. Nature 434: 913–917PubMedCrossRefGoogle Scholar
  85. 85.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917–921PubMedCrossRefGoogle Scholar
  86. 86.
    Kraakman-van der Zwet M, Overkamp WJ, van Lange RE, Essers J, van Duijn-Goedhart A, Wiggers I, Swaminathan S, van Buul PP, Errami A et al (2002) Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions. Mol Cell Biol 22: 669–679CrossRefGoogle Scholar
  87. 87.
    Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362: 709–715PubMedCrossRefGoogle Scholar
  88. 88.
    Griffin CS, Simpson PJ, Wilson CR, Thacker J (2000) Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nat Cell Biol 2: 757–761PubMedCrossRefGoogle Scholar
  89. 89.
    Tebbs RS, Zhao Y, Tucker JD, Scheerer JB, Siciliano MJ, Hwang M, Liu N, Legerski RJ, Thompson LH (1995) Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene. Proc Natl Acad Sci USA 92: 6354–6358PubMedCrossRefGoogle Scholar
  90. 90.
    Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108: 171–182Google Scholar
  91. 91.
    Gallmeier E, Kern SE (2005) Absence of specific cell killing of the BRCA2-deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition. Cancer Biol Ther 4: 703–706PubMedGoogle Scholar
  92. 92.
    McCabe N, Lord CJ, Tutt AN, Martin NM, Smith GC, Ashworth A (2005) BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: An issue of potency. Cancer Biol Ther 4: 934–936PubMedCrossRefGoogle Scholar
  93. 93.
    Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451: 1111–1115PubMedCrossRefGoogle Scholar
  94. 94.
    Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE, Lee EY (1999) BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 59: 3547–3551PubMedGoogle Scholar
  95. 95.
    Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK (2000) The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275: 23899–23903PubMedCrossRefGoogle Scholar
  96. 96.
    Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ et al (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451: 1116–1120PubMedCrossRefGoogle Scholar
  97. 97.
    Lindqvist A, Kallstrom H, Lundgren A, Barsoum E, Rosenthal CK (2005) Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk1 at the centrosome. J Cell Biol 171: 35–45PubMedCrossRefGoogle Scholar
  98. 98.
    Paulovich AG, Toczyski DP, Hartwell LH (1997) When checkpoints fail. Cell 88: 315–321PubMedCrossRefGoogle Scholar
  99. 99.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) P53 mutations in human cancers. Science 253: 49–53PubMedCrossRefGoogle Scholar
  100. 100.
    Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H (1997) Mitotic and G2 checkpoint control: Regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277: 1501–1505PubMedCrossRefGoogle Scholar
  101. 101.
    Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (1997) Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk regulation through Cdc25. Science 277: 1497–1501PubMedCrossRefGoogle Scholar
  102. 102.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15: 2177–2196PubMedCrossRefGoogle Scholar
  103. 103.
    Mailand N, Podtelejnikov AV, Groth A, Mann M, Bartek J, Lukas J (2002) Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. EMBO J 21: 5911–5920PubMedCrossRefGoogle Scholar
  104. 104.
    Zhao H, Watkins JL, Piwnica-Worms H (2002) Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci USA 99: 14795–14800PubMedCrossRefGoogle Scholar
  105. 105.
    Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H (2003) Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem 278: 21767–21773PubMedCrossRefGoogle Scholar
  106. 106.
    Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59: 4375–4382PubMedGoogle Scholar
  107. 107.
    Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79: 2942–2946PubMedCrossRefGoogle Scholar
  108. 108.
    Fingert HJ, Chang JD, Pardee AB (1986) Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res 46: 2463–2467PubMedGoogle Scholar
  109. 109.
    Powell SN, DeFrank JS, Connell P, Eogan M, Preffer F, Dombkowski D, Tang W, Friend S (1995) Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 55: 1643–1648PubMedGoogle Scholar
  110. 110.
    Lock RB, Galperina OV, Feldhoff RC, Rhodes LJ (1994) Concentration-dependent differences in the mechanisms by which caffeine potentiates etoposide cytotoxicity in HeLa cells. Cancer Res 54: 4933–4939Google Scholar
  111. 111.
    Fan S, Smith ML, Rivet DJ, 2nd, Duba D, Zhan Q, Kohn KW, Fornace AJ Jr, O’Connor PM (1995) Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res 55: 1649–1654PubMedGoogle Scholar
  112. 112.
    Serafin AM, Binder AB, Bohm L (2001) Chemosensitivity of prostatic tumour cell lines under conditions of G2 block abrogation. Urol Res 29: 221–227PubMedCrossRefGoogle Scholar
  113. 113.
    Busby EC, Leistritz DF, Abraham RT, Karnitz LM, Sarkaria JN (2000) The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res 60: 2108–2112PubMedGoogle Scholar
  114. 114.
    Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O’Connor PM, Piwnica-Worms H (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275: 5600–5605PubMedCrossRefGoogle Scholar
  115. 115.
    Yu Q, La Rose J, Zhang H, Takemura H, Kohn KW, Pommier Y (2002) UCN-01 inhibits p53 upregulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res 62: 5743–5748PubMedGoogle Scholar
  116. 116.
    Sato S, Fujita N, Tsuruo T (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21: 1727–1738PubMedCrossRefGoogle Scholar
  117. 117.
    Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) P53-deficient cells rely on ATM-and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11: 175–189PubMedCrossRefGoogle Scholar
  118. 118.
    Wang Q, Fan S, Eastman A,Worland PJ, Sausville EA, O’Connor PM (1996) UCN-01: A potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 88: 956–965PubMedCrossRefGoogle Scholar
  119. 119.
    R. Sanchez-Olea et al. 119 Yao SL, Akhtar AJ, McKenna KA, Bedi GC, Sidransky D, Mabry M, Ravi R, Collector MI, Jones RJ, Sharkis SJ et al (1996) Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase. Nat Med 2: 1140–1143CrossRefGoogle Scholar
  120. 120.
    Bulavin DV, Higashimoto Y, Popoff IJ, Gaarde WA, Basrur V, Potapova O, Appella E, Fornace AJ Jr, (2001) Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411: 102–107PubMedCrossRefGoogle Scholar
  121. 121.
    Mikhailov A, Shinohara M, Rieder CL (2004) Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway. J Cell Biol 166: 517–526Google Scholar
  122. 122.
    Karlsson C, Katich S, Hagting A, Hoffmann I, Pines J (1999) Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J Cell Biol 146: 573–584PubMedCrossRefGoogle Scholar
  123. 123.
    Bulavin DV, Amundson SA, Fornace AJ (2002) P38 and Chk1 kinases: Different conductors for the G(2)/M checkpoint symphony. Curr Opin Genet Dev 12: 92–97PubMedCrossRefGoogle Scholar
  124. 124.
    Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB (2005) MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell 17: 37–48PubMedCrossRefGoogle Scholar
  125. 125.
    Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907–913PubMedCrossRefGoogle Scholar
  126. 126.
    Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870PubMedCrossRefGoogle Scholar
  127. 127.
    Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319: 1352–1355PubMedCrossRefGoogle Scholar
  128. 128.
    Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC et al (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444: 633–637PubMedCrossRefGoogle Scholar
  129. 129.
    Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre M, Nuciforo PG, Bensimon A et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444: 638–642CrossRefGoogle Scholar
  130. 130.
    Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Roberto Sánchez-Olea
    • 1
  • Mónica R. Calera
    • 1
  • Alexei Degterev
    • 2
  1. 1.Instituto de FísicaUniversidad Autónoma de San Luis PotosíMexico
  2. 2.Department of BiochemistryTufts University School of MedicineBostonUSA

Personalised recommendations