DNA Damage and Polyploidization

  • Jeremy P.H. Chow
  • Randy Y.C. Poon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 676)


A growing body of evidence indicates that polyploidization triggers chromosomal instability and contributes to tumorigenesis. DNA damage is increasingly being recognized for its roles in promoting polyploidization. Although elegant mechanisms known as the DNA damage checkpoints are responsible for halting the cell cycle after DNA damage, agents that uncouple the checkpoints can induce unscheduled entry into mitosis. Likewise, defects of the checkpoints in several disorders permit mitotic entry even in the presence of DNA damage. Forcing cells with damaged DNA into mitosis causes severe chromosome segregation defects, including lagging chromosomes, chromosomal fragments and chromosomal bridges. The presence of these lesions in the cleavage plane is believed to abort cytokinesis. It is postulated that if cytokinesis failure is coupled with defects of the p53-dependent postmitotic checkpoint pathway, cells can enter S phase and become polyploids. Progress in the past several years has unraveled some of the underlying principles of these pathways and underscored the important role of DNA damage in polyploidization. Furthermore, polyploidization per se may also be an important determinant of sensitivity to DNA damage, thereby may offer an opportunity for novel therapies.


Mitotic Catastrophe Polyploid Cell Nijmegen Breakage Syndrome Tetraploid Cell Multipolar Mitosis 
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.
    Duesberg P, Li R. Multistep carcinogenesis: a chain reaction of aneuploidizations. Cell Cycle 2003; 2(3):202–210.PubMedCrossRefGoogle Scholar
  2. 2.
    Boveri T. Concerning the Origin of Malignant Tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 2008; 121(1):S1–S84.CrossRefGoogle Scholar
  3. 3.
    Sotillo R, Hernando E, Diaz-Rodriguez E et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 2007; 11(1):9–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Weaver BA, Silk AD, Montagna C et al. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 2007; 11(1):25–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Woo RA, Poon RYC. Gene mutations and aneuploidy: the instability that causes cancer. Cell Cycle 2004; 3(9):1101–1103.PubMedCrossRefGoogle Scholar
  6. 6.
    Storchova Z, Kuffer C. The consequences of tetraploidy and aneuploidy. J Cell Sci 2008; 121(Pt 23):3859–3866.PubMedCrossRefGoogle Scholar
  7. 7.
    Barrett MT, Pritchard D, Palanca-Wessels C et al. Molecular phenotype of spontaneously arising 4N (G2-tetraploid) intermediates of neoplastic progression in Barrett’s esophagus. Cancer Res 2003; 63(14):4211–4217.PubMedGoogle Scholar
  8. 8.
    Galipeau PC, Cowan DS, Sanchez CA et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations and progression to aneuploidy in Barrett’s esophagus. Proc Natl Acad Sci USA 1996; 93(14):7081–7084.PubMedCrossRefGoogle Scholar
  9. 9.
    Maley CC. Multistage carcinogenesis in Barrett’s esophagus. Cancer Lett 2007; 245(1–2):22–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Stiff T, O’Driscoll M, Rief N et al. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 2004; 64(7):2390–2396.PubMedCrossRefGoogle Scholar
  11. 11.
    Olaharski AJ, Sotelo R, Solorza-Luna G et al. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 2006; 27(2):337–343.PubMedCrossRefGoogle Scholar
  12. 12.
    Mayer VW, Aguilera A. High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mutat Res 1990; 231(2):177–186.PubMedGoogle Scholar
  13. 13.
    Storchova Z, Breneman A, Cande J et al. Genome-wide genetic analysis of polyploidy in yeast. Nature 2006; 443(7111):541–547.PubMedCrossRefGoogle Scholar
  14. 14.
    Cowell JK. Consistent chromosome abnormalities associated with mouse bladder epithelial cell lines transformed in vitro. J Natl Cancer Inst 1980; 65(5):955–961.PubMedGoogle Scholar
  15. 15.
    Fujiwara T, Bandi M, Nitta M et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005; 437(7061):1043–1047.PubMedCrossRefGoogle Scholar
  16. 16.
    Duelli D, Lazebnik Y. Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer 2007; 7(12):968–976.PubMedCrossRefGoogle Scholar
  17. 17.
    Nowell PC. The clonal evolution of tumor cell populations. Science 1976; 194(4260):23–28.PubMedCrossRefGoogle Scholar
  18. 18.
    Ohno S. Evolution by gene duplication. New York, Springer-Verlag, 1970.Google Scholar
  19. 19.
    Furlong RF, Holland PW. Were vertebrates octoploid? Philos Trans R Soc Lond B Biol Sci 2002; 357(1420):531–544.PubMedCrossRefGoogle Scholar
  20. 20.
    Senovilla L, Vitale I, Galluzzi L et al. p53 represses the polyploidization of primary mammary epithelial cells by activating apoptosis. Cell Cycle 2009; 8(9):1380–1385.PubMedCrossRefGoogle Scholar
  21. 21.
    Shi Q, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005; 437(7061):1038–1042.PubMedCrossRefGoogle Scholar
  22. 22.
    Nigg EA. Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2(11):815–825.PubMedCrossRefGoogle Scholar
  23. 23.
    Gergely F, Basto R. Multiple centrosomes: together they stand, divided they fall. Genes Dev 2008; 22(17):2291–2296.PubMedCrossRefGoogle Scholar
  24. 24.
    Basto R, Brunk K, Vinadogrova T et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 2008; 133(6):1032–1042.PubMedCrossRefGoogle Scholar
  25. 25.
    Borel F, Lohez OD, Lacroix FB et al. Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells. Proc Natl Acad Sci USA 2002; 99(15):9819–9824.PubMedCrossRefGoogle Scholar
  26. 26.
    Kwon M, Godinho SA, Chandhok NS et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 2008; 22(16):2189–2203.PubMedCrossRefGoogle Scholar
  27. 27.
    Quintyne NJ, Reing JE, Hoffelder DR et al. Spindle multipolarity is prevented by centrosomal clustering. Science 2005; 307(5706):127–129.PubMedCrossRefGoogle Scholar
  28. 28.
    Yang Z, Loncarek J, Khodjakov A et al. Extra centrosomes and/or chromosomes prolong mitosis in human cells. Nat Cell Biol 2008; 10(6):748–751.PubMedCrossRefGoogle Scholar
  29. 29.
    Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature 2009; 460(7252):278–282.PubMedCrossRefGoogle Scholar
  30. 30.
    Barski G, Sorieul S, Cornefert F. [Production of cells of a “hybrid” nature in culturs in vitro of 2 cellular strains in combination.]. C R Hebd Seances Acad Sci 1960; 251:1825–1827.PubMedGoogle Scholar
  31. 31.
    Goldenberg DM, Pavia RA, Tsao MC. In vivo hybridisation of human tumour and normal hamster cells. Nature 1974; 250(5468):649–651.PubMedCrossRefGoogle Scholar
  32. 32.
    Pawelek JM. Tumour-cell fusion as a source of myeloid traits in cancer. Lancet Oncol 2005; 6(12):988–993.PubMedCrossRefGoogle Scholar
  33. 33.
    Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007; 8(5):379–393.PubMedCrossRefGoogle Scholar
  34. 34.
    Rieder CL, Maiato H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 2004; 7(5):637–651.PubMedCrossRefGoogle Scholar
  35. 35.
    Weaver BA, Cleveland DW. Decoding the links between mitosis, cancer and chemotherapy: The mitotic checkpoint, adaptation and cell death. Cancer Cell 2005; 8(1):7–12.PubMedCrossRefGoogle Scholar
  36. 36.
    Brito DA, Rieder CL. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol 2006; 16(12):1194–1200.PubMedCrossRefGoogle Scholar
  37. 37.
    Lanni JS, Jacks T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol Cell Biol 1998; 18(2):1055–]ReferencesPubMedGoogle Scholar
  38. 38.
    Chan YW, On KF, Chan WM et al. The kinetics of p53 activation versus cyclin E accumulation underlies the relationship between the spindle-assembly checkpoint and the postmitotic checkpoint. J Biol Chem 2008; 283(231):15716–15723.PubMedCrossRefGoogle Scholar
  39. 39.
    Liu Y, Heilman SA, Illanes D et al. p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Cancer Res 2007; 67(6):2603–2610.PubMedCrossRefGoogle Scholar
  40. 40.
    Vogel C, Kienitz A, Hofmann I et al. Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy. Oncogene 2004; 23(41):6845–6853.PubMedCrossRefGoogle Scholar
  41. 41.
    Steigemann P, Wurzenberger C, Schmitz MH et al. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell 2009; 136(3):473–484.PubMedCrossRefGoogle Scholar
  42. 42.
    Cimini D, Mattiuzzo M, Torosantucci L et al. Histone hyperacetylation in mitosis prevents sister chromatid separation and produces chromosome segregation defects. Mol Biol Cell 2003; 14(9):3821–3833.PubMedCrossRefGoogle Scholar
  43. 43.
    Gisselsson D, Pettersson L, Hoglund M et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci USA 2000; 97(10):5357–5362.PubMedCrossRefGoogle Scholar
  44. 44.
    Andreassen PR, Lohez OD, Lacroix FB et al. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol Biol Cell 2001; 12(5):1315–1328.PubMedGoogle Scholar
  45. 45.
    Uetake Y, Loncarek J, Nordberg JJ et al. Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells. J Cell Biol 2007; 176(2):173–182.PubMedCrossRefGoogle Scholar
  46. 46.
    Wong C, Stearns T. Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number and cytokinesis failure. BMC Cell Biol 2005; 6(1):6.PubMedCrossRefGoogle Scholar
  47. 47.
    Dalton WB, Nandan MO, Moore RT et al. Human cancer cells commonly acquire DNA damage during mitotic arrest. Cancer Res 2007; 67(24):11487–11492.PubMedCrossRefGoogle Scholar
  48. 48.
    Quignon F, Rozier L, Lachages AM et al. Sustained mitotic block elicits DNA breaks: one-step alteration of ploidy and chromosome integrity in mammalian cells. Oncogene 2007; 26(2):165–172.PubMedCrossRefGoogle Scholar
  49. 49.
    Blagosklonny MV. Prolonged mitosis versus tetraploid checkpoint: how p53 measures the duration of mitosis. Cell Cycle 2006; 5(9):971–975.PubMedCrossRefGoogle Scholar
  50. 50.
    Grafi G, Larkins BA. Endoreduplication in Maize Endosperm: Involvement of M Phase—Promoting Factor Inhibition and Induction of S Phase—Related Kinases. Science 1995; 269(5228):1262–1264.PubMedCrossRefGoogle Scholar
  51. 51.
    Sigrist SJ, Lehner CF. Drosophila fizzy-related down-regulates mitotic cyclins and is required for cell proliferation arrest and entry into endocycles. Cell 1997; 90(4):671–681.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Y, Wang Z, Liu DX et al. Ubiquitin-dependent degradation of cyclin B is accelerated in polyploid megakaryocytes. J Biol Chem 1998; 273(3):1387–1392.PubMedCrossRefGoogle Scholar
  53. 53.
    Itzhaki JE, Gilbert CS, Porter AC. Construction by gene targeting in human cells of a “conditional” CDC2 mutant that rereplicates its DNA. Nat Genet 1997; 15(3):258–265.PubMedCrossRefGoogle Scholar
  54. 54.
    Di Fiore B, Pines J. Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. J Cell Biol 2007; 177(3):425–437.PubMedCrossRefGoogle Scholar
  55. 55.
    Machida YJ, Dutta A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev 2007; 21(2):184–194.PubMedCrossRefGoogle Scholar
  56. 56.
    Woo RA, Poon RY. Cyclin-dependent kinases and S phase control in mammalian cells. Cell Cycle 2003; 2(4):316–324.PubMedCrossRefGoogle Scholar
  57. 57.
    Parrilla-Castellar ER, Arlander SJ, Karnitz L. Dial 9-1-1 for DNA damage: the Rad9-Hus1-Rad1 (9-1-1) clamp complex. DNA Repair (Amst) 2004; 3(8–9):1009–1014.CrossRefGoogle Scholar
  58. 58.
    Jhanwar-Uniyal M. BRCA1 in cancer, cell cycle and genomic stability. Front Biosci 2003; 8:s1107–17.CrossRefGoogle Scholar
  59. 59.
    Wang Y, Cortez D, Yazdi P et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000; 14(8):927–939.PubMedCrossRefGoogle Scholar
  60. 60.
    Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 2008; 9(8):616–627.PubMedCrossRefGoogle Scholar
  61. 61.
    Petermann E, Caldecott KW. Evidence that the ATR/Chk1 pathway maintains normal replication fork progression during unperturbed S phase. Cell Cycle 2006; 5(19):2203–2209.PubMedCrossRefGoogle Scholar
  62. 62.
    Freire R, van Vugt MA, Mamely I et al. Claspin: timing the cell cycle arrest when the genome is damaged. Cell Cycle 2006; 5(24):2831–2834.PubMedCrossRefGoogle Scholar
  63. 63.
    Bassermann F, Frescas D, Guardavaccaro D et al. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 2008; 134(2):256–267.PubMedCrossRefGoogle Scholar
  64. 64.
    Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 2006; 18(2):185–191.PubMedCrossRefGoogle Scholar
  65. 65.
    Chen Y, Poon RY. The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability. Front Biosci 2008; 13:5016–5029.PubMedGoogle Scholar
  66. 66.
    Boutros R, Lobjois V, Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 2007; 7(7):495–507.PubMedCrossRefGoogle Scholar
  67. 67.
    Lee J, Kumagai A, Dunphy WG. Positive regulation of Wee1 by Chk1 and 14-3-3 proteins. Mol Biol Cell 2001; 12(3):551–563.PubMedGoogle Scholar
  68. 68.
    Rothblum-Oviatt CJ, Ryan CE, Piwnica-Worms H. 14-3-3 binding regulates catalytic activity of human Wee1 kinase. Cell Growth Differ 2001; 12(12):581–589.PubMedGoogle Scholar
  69. 69.
    Chan TA, Hermeking H, Lengauer C et al. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 1999; 401(6753):616–620.PubMedCrossRefGoogle Scholar
  70. 70.
    Zdzienicka MZ. Mammalian X ray sensitive mutants: a tool for the elucidation of the cellular response to ionizing radiation. Cancer Surv 1996; 28:281–293.PubMedGoogle Scholar
  71. 71.
    Rhind N, Russell P. Checkpoints: it takes more than time to heal some wounds. Curr Biol 2000; 10(24):R908–11.PubMedCrossRefGoogle Scholar
  72. 72.
    Falck J, Mailand N, Syljuasen RG et al. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 2001; 410(6830):842–847.PubMedCrossRefGoogle Scholar
  73. 73.
    Sorensen CS, Syljuasen RG, Falck J et al. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 2003; 3(3):247–258.PubMedCrossRefGoogle Scholar
  74. 74.
    Falck J, Petrini JH, Williams BR et al. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet 2002; 30(3):290–294.PubMedCrossRefGoogle Scholar
  75. 75.
    Jessberger R, Riwar B, Baechtold H et al. SMC proteins constitute two subunits of the mammalian recombination complex RC-1. EMBO J 1996; 15(15):4061–4068.PubMedGoogle Scholar
  76. 76.
    Michaelis C, Ciosk R, Nasmyth K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 1997; 91(1):35–45.PubMedCrossRefGoogle Scholar
  77. 77.
    Kim ST, Xu B, Kastan MB. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev 2002; 16(5):560–570.PubMedCrossRefGoogle Scholar
  78. 78.
    Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death Differ 2006; 13(6):1027–1036.PubMedCrossRefGoogle Scholar
  79. 79.
    Chehab NH, Malikzay A, Stavridi ES et al. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci USA 1999; 96(24):13777–13782.PubMedCrossRefGoogle Scholar
  80. 80.
    Shieh SY, Ikeda M, Taya Y et al. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1997; 91(3):325–334.PubMedCrossRefGoogle Scholar
  81. 81.
    Chehab NH, Malikzay A, Appel M et al. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 2000; 14(3):278–288.PubMedGoogle Scholar
  82. 82.
    Hirao A, Kong YY, Matsuoka S et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 2000; 287(5459):1824–1827.PubMedCrossRefGoogle Scholar
  83. 83.
    Shieh SY, Ahn J, Tamai K et al. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 2000; 14(3):289–300.PubMedGoogle Scholar
  84. 84.
    Bunz F, Dutriaux A, Lengauer C et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282(5393):1497–1501.PubMedCrossRefGoogle Scholar
  85. 85.
    Lee J, Kim JA, Barbier V et al. DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest. Mol Biol Cell 2009; 20(7):1891–1902.PubMedCrossRefGoogle Scholar
  86. 86.
    Andreassen PR, Lacroix FB, Lohez OD et al. Neither p21WAF1 nor 14-3-3sigma prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells. Cancer Res 2001; 61(20):7660–7668.PubMedGoogle Scholar
  87. 87.
    Chu K, Teele N, Dewey MW et al. Computerized video time lapse study of cell cycle delay and arrest, mitotic catastrophe, apoptosis and clonogenic survival in irradiated 14-3-3sigma and CDKN1A (p21) knockout cell lines. Radiat Res 2004; 162(3):270–286.PubMedCrossRefGoogle Scholar
  88. 88.
    Ivanov A, Cragg MS, Erenpreisa J et al. Endopolyploid cells produced after severe genotoxic damage have the potential to repair DNA double strand breaks. J Cell Sci 2003; 116(Pt 20):4095–4106.PubMedCrossRefGoogle Scholar
  89. 89.
    Bohm N, Sandritter W. DNA in human tumors: a cytophotometric study. Curr Top Pathol 1975; 60:151–219.PubMedGoogle Scholar
  90. 90.
    Blagosklonny MV. Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal. Leukemia 1999; 13(12):2031–2035.PubMedCrossRefGoogle Scholar
  91. 91.
    Puig PE, Guilly MN, Bouchot A et al. Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy. Cell Biol Int 2008; 32(9):1031–1043.PubMedCrossRefGoogle Scholar
  92. 92.
    Nitta M, Kobayashi O, Honda S et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene 2004; 23(39):6548–6558.PubMedCrossRefGoogle Scholar
  93. 93.
    Decordier I, Kirsch-Volders M. The in vitro micronucleus test: from past to future. Mutat Res 2006; 607(1):2–4.PubMedGoogle Scholar
  94. 94.
    Acilan C, Potter DM, Saunders WS. DNA repair pathways involved in anaphase bridge formation. Genes Chromosomes Cancer 2007; 46(6):522–531.PubMedCrossRefGoogle Scholar
  95. 95.
    Fingert HJ, Chang JD, Pardee AB. Cytotoxic, cell cycle and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res 1986; 46(5):2463–2467.PubMedGoogle Scholar
  96. 96.
    Chang BD, Broude EV, Fang J et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 2000; 19(17):2165–2170.PubMedCrossRefGoogle Scholar
  97. 97.
    Castedo M, Perfettini JL, Roumier T et al. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004; 23(16):2825–2837.PubMedCrossRefGoogle Scholar
  98. 98.
    Vogel C, Hager C, Bastians H. Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. Cancer Res 2007; 67(1):339–345.PubMedCrossRefGoogle Scholar
  99. 99.
    Lavin MF, Khanna KK. ATM: the protein encoded by the gene mutated in the radiosensitive syndrome ataxia-telangiectasia. Int J Radiat Biol 1999; 75(10):1201–1214.PubMedCrossRefGoogle Scholar
  100. 100.
    Takai H, Naka K, Okada Y et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J 2002; 21(19):5195–5205.PubMedCrossRefGoogle Scholar
  101. 101.
    Lam MH, Liu Q, Elledge SJ et al. Chk1 is haploinsufficient for multiple functions critical to tumor suppression. Cancer Cell 2004; 6(1):45–59.PubMedCrossRefGoogle Scholar
  102. 102.
    Niida H, Tsuge S, Katsuno Y et al. Depletion of Chk1 leads to premature activation of Cdc2-cyclin B and mitotic catastrophe. J Biol Chem 2005; 280(47):39246–39252.PubMedCrossRefGoogle Scholar
  103. 103.
    Blasina A, Paegle ES, McGowan CH. The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells. Mol Biol Cell 1997; 8(6):1013–1023.PubMedGoogle Scholar
  104. 104.
    Chow JPH, Siu WY, Ho HTB et al. Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints. J Biol Chem 2003; 278(42):40815–40828.PubMedCrossRefGoogle Scholar
  105. 105.
    Blasina A, Price BD, Turenne GA et al. Caffeine inhibits the checkpoint kinase ATM. Curr Biol 1999; 9(19):1135–1138.PubMedCrossRefGoogle Scholar
  106. 106.
    Hall-Jackson CA, Cross DA, Morrice N et al. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene 1999; 18(48):6707–6713.PubMedCrossRefGoogle Scholar
  107. 107.
    Sarkaria JN, Busby EC, Tibbetts RS et al. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 1999; 59(17):4375–4382.PubMedGoogle Scholar
  108. 108.
    Wang Q, Fan S, Eastman A et al. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 1996; 88(14):956–965.PubMedCrossRefGoogle Scholar
  109. 109.
    Graves PR, Yu L, Schwarz JK et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 2000; 275(8):5600–5605.PubMedCrossRefGoogle Scholar
  110. 110.
    Tse AN, Schwartz GK. Potentiation of cytotoxicity of topoisomerase i poison by concurrent and sequential treatment with the checkpoint inhibitor UCN-01 involves disparate mechanisms resulting in either p53-independent clonogenic suppression or p53-dependent mitotic catastrophe. Cancer Res 2004; 64(18):6635–6644.PubMedCrossRefGoogle Scholar
  111. 111.
    Busby EC, Leistritz DF, Abraham RT et al. The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res 2000; 60(8):2108–2112.PubMedGoogle Scholar
  112. 112.
    Castedo M, Perfettini JL, Roumier T et al. The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Oncogene 2004; 23(25):4353–4361.PubMedCrossRefGoogle Scholar
  113. 113.
    Carney JP, Maser RS, Olivares H et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 1998; 93(3):477–486.PubMedCrossRefGoogle Scholar
  114. 114.
    Luo G, Yao MS, Bender CF et al. Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 1999; 96(13):7376–7381.PubMedCrossRefGoogle Scholar
  115. 115.
    Xiao Y, Weaver DT. Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. Nucleic Acids Res 1997; 25(15):2985–2991.PubMedCrossRefGoogle Scholar
  116. 116.
    Zhu J, Petersen S, Tessarollo L et al. Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 2001; 11(2):105–109.PubMedCrossRefGoogle Scholar
  117. 117.
    Williams BR, Mirzoeva OK, Morgan WF et al. A murine model of Nijmegen breakage syndrome. Curr Biol 2002; 12(8):648–653.PubMedCrossRefGoogle Scholar
  118. 118.
    Reina-San-Martin B, Nussenzweig MC, Nussenzweig A et al. Genomic instability, endoreduplication and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci USA 2005; 102(5):1590–1595.PubMedCrossRefGoogle Scholar
  119. 119.
    Perry MB, Lehman JM. Activities of SV40 T antigen necessary for the induction of tetraploid DNA content in permissive CV-1 cells. Cytometry 1998; 31(4):251–259.PubMedCrossRefGoogle Scholar
  120. 120.
    Wu X, Avni D, Chiba T et al. SV40 T antigen interacts with Nbs1 to disrupt DNA replication control. Genes Dev 2004; 18(11):1305–1316.PubMedCrossRefGoogle Scholar
  121. 121.
    Castedo M, Coquelle A, Vivet S et al. Apoptosis regulation in tetraploid cancer cells. EMBO J 2006; 25(11):2584–2595.PubMedCrossRefGoogle Scholar
  122. 122.
    Hau PM, Siu WY, Wong N et al. Polyploidization increases the sensitivity to DNA-damaging agents in mammalian cells. FEBS Lett 2006; 580(19):4727–4736.PubMedCrossRefGoogle Scholar
  123. 123.
    Mable BK, Otto SP. Masking and purging mutations following EMS treatment in haploid, diploid and tetraploid yeast (Saccharomyces cerevisiae). Genet Res 2001; 77(1):9–26.PubMedCrossRefGoogle Scholar
  124. 124.
    Nagy A, Gocza E, Diaz EM et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 1990; 110(3):815–821.PubMedGoogle Scholar
  125. 125.
    Castedo M, Coquelle A, Vitale I et al. Selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis. Ann N Y Acad Sci 2006; 1090:35–49.PubMedCrossRefGoogle Scholar
  126. 126.
    Gregory TR. Coincidence, coevolution, or causation? DNA content, cell size and the C-value enigma. Biol Rev Camb Philos Soc 2001; 76(1):65–101.PubMedCrossRefGoogle Scholar
  127. 127.
    Nurse P. The genetic control of cell volume. In: Cavalier-Smith T, ed. The Evolution of Genome Size. Hoboken: John Wiley and Sons, 1985:185–196.Google Scholar
  128. 128.
    Henery CC, Bard JB, Kaufman MH. Tetraploidy in mice, embryonic cell number and the grain of the developmental map. Dev Biol 1992; 152(2):233–241.PubMedCrossRefGoogle Scholar
  129. 129.
    Comai L. The advantages and disadvantages of being polyploid. Nat Rev Genet 2005; 6(11):836–846.PubMedCrossRefGoogle Scholar
  130. 130.
    Hunt T. You never know: Cdk inhibitors as anti-cancer drugs. Cell Cycle 2008; 7(24):3789–3790.PubMedCrossRefGoogle Scholar
  131. 131.
    Chan YW, Ma HT, Wong W et al. CDK1 inhibitors antagonize the immediate apoptosis triggered by spindle disruption but promote apoptosis following the subsequent rereplication and abnormal mitosis. Cell Cycle 2008; 7(10):1449–1461.PubMedCrossRefGoogle Scholar
  132. 132.
    Fischer PM, Gianella-Borradori A. Recent progress in the discovery and development of cyclin-dependent kinase inhibitors. Expert Opin Investig Drugs 2005; 14(4):457–477.PubMedCrossRefGoogle Scholar
  133. 133.
    Therman E, Kuhn EM. Mitotic modifications and aberrations in cancer. Crit Rev Oncog 1989; 1(3):293–305.PubMedGoogle Scholar
  134. 134.
    Erenpreisa J, Cragg MS. Mitotic death: a mechanism of survival? A review. Cancer Cell Int 2001; 1(1):1.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Department of BiochemistryHong Kong University of Science and TechnologyHong KongChina

Personalised recommendations