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Checkpoint kinase 1 in DNA damage response and cell cycle regulation

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Abstract

Originally identified as a mediator of DNA damage response (DDR), checkpoint kinase 1 (Chk1) has a broader role in checkpoint activation in DDR and normal cell cycle regulation. Chk1 activation involves phosphorylation at conserved sites. However, recent work has identified a splice variant of Chk1, which may regulate Chk1 in both DDR and normal cell cycle via molecular interaction. Upon activation, Chk1 phosphorylates a variety of substrate proteins, resulting in the activation of DNA damage checkpoints, cell cycle arrest, DNA repair, and/or cell death. Chk1 and its related signaling may be an effective therapeutic target in diseases such as cancer.

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Abbreviations

Chk1:

Checkpoint kinase 1

Chk2:

Checkpoint kinase 2

Chk1:

S-checkpoint kinase 1-short

DDR:

DNA damage response

ATM:

Ataxia telangiectasia mutated

ATR:

ATM and Rad3 related

Cdc25:

Cell division cycle 25

CDK:

Cyclin-dependent kinases

References

  1. Walworth N, Davey S, Beach D (1993) Fission yeast Chk1-protein kinase links the rad checkpoint pathway to Cdc2. Nature 363:368–371

    PubMed  CAS  Google Scholar 

  2. Kumagai A, Guo Z, Emami KH, Wang SX, Dunphy WG (1998) The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts. J Cell Biol 142:1559–1569

    PubMed  CAS  Google Scholar 

  3. Fogarty P, Kalpin RF, Sullivan W (1994) The Drosophila maternal-effect mutation grapes causes a metaphase arrest at nuclear cycle 13. Development 120:2131–2142

    PubMed  CAS  Google Scholar 

  4. 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 277:1501–1505

    PubMed  CAS  Google Scholar 

  5. Elledge SJ (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274:1664–1672

    PubMed  CAS  Google Scholar 

  6. Nurse P (2000) A long twentieth century of the cell cycle and beyond. Cell 100:71–78

    PubMed  CAS  Google Scholar 

  7. Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9:616–627

    PubMed  CAS  Google Scholar 

  8. Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16:376–383

    PubMed  CAS  Google Scholar 

  9. Bartek J, Lukas J (2007) DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol 19:238–245

    PubMed  CAS  Google Scholar 

  10. Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308:551–554

    PubMed  CAS  Google Scholar 

  11. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    PubMed  CAS  Google Scholar 

  12. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85

    PubMed  CAS  Google Scholar 

  13. Nam EA, Cortez D (2011) ATR signalling: more than meeting at the fork. Biochem J 436:527–536

    PubMed  CAS  Google Scholar 

  14. Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–1548

    PubMed  CAS  Google Scholar 

  15. Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294:1713–1716

    PubMed  CAS  Google Scholar 

  16. Parrilla-Castellar ER, Arlander SJ, Karnitz L (2004) Dial 9–1-1 for DNA damage: the Rad9-Hus1-Rad1 (9–1-1) clamp complex. DNA Repair 3:1009–1014

    PubMed  CAS  Google Scholar 

  17. Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM (2007) The Rad9-Hus1-Rad1 (9–1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21:1472–1477

    PubMed  CAS  Google Scholar 

  18. Lee J, Kumagai A, Dunphy WG (2007) The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem 282:28036–28044

    PubMed  CAS  Google Scholar 

  19. Pabla N, Ma Z, McIlhatton MA, Fishel R, Dong Z (2011) hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. J Biol Chem 286:10411–10418

    PubMed  CAS  Google Scholar 

  20. Kumagai A, Dunphy WG (2000) Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol Cell 6:839–849

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  22. Stiff T, Walker SA, Cerosaletti K, Goodarzi AA, Petermann E, Concannon P, O’Driscoll M, Jeggo PA (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J 25:5775–5782

    PubMed  CAS  Google Scholar 

  23. Pabla N, Huang S, Mi QS, Daniel R, Dong Z (2008) ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem 283:6572–6583

    PubMed  CAS  Google Scholar 

  24. Enders GH (2008) Expanded roles for Chk1 in genome maintenance. J Biol Chem 283:17749–17752

    PubMed  CAS  Google Scholar 

  25. Sorensen CS, Syljuasen RG (2012) Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res 40:477–486

    PubMed  CAS  Google Scholar 

  26. Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14:397–402

    PubMed  CAS  Google Scholar 

  27. de Klein A, Muijtjens M, van Os R, Verhoeven Y, Smit B, Carr AM, Lehmann AR, Hoeijmakers JH (2000) Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol 10:479–482

    PubMed  Google Scholar 

  28. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14:1448–1459

    PubMed  CAS  Google Scholar 

  29. Takai H, Tominaga K, Motoyama N, Minamishima YA, Nagahama H, Tsukiyama T, Ikeda K, Nakayama K, Nakanishi M (2000) Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice. Genes Dev 14:1439–1447

    PubMed  CAS  Google Scholar 

  30. Fogarty P, Campbell SD, Abu-Shumays R, Phalle BS, Yu KR, Uy GL, Goldberg ML, Sullivan W (1997) The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity. Curr Biol 7:418–426

    PubMed  CAS  Google Scholar 

  31. Purdy A, Uyetake L, Cordeiro MG, Su TT (2005) Regulation of mitosis in response to damaged or incompletely replicated DNA require different levels of Grapes (Drosophila Chk1). J Cell Sci 118:3305–3315

    PubMed  CAS  Google Scholar 

  32. Royou A, McCusker D, Kellogg DR, Sullivan W (2008) Grapes(Chk1) prevents nuclear CDK1 activation by delaying cyclin B nuclear accumulation. J Cell Biol 183:63–75

    PubMed  CAS  Google Scholar 

  33. Syljuasen RG, Sorensen CS, Hansen LT, Fugger K, Lundin C, Johansson F, Helleday T, Sehested M, Lukas J, Bartek J (2005) Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol Cell Biol 25:3553–3562

    PubMed  CAS  Google Scholar 

  34. Zachos G (2003) Chk1-defcient tumour cells are viable but exhibit multiple checkpoint and survival defects. EMBO Rep 22(3):713–723

    CAS  Google Scholar 

  35. Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3:247–258

    PubMed  CAS  Google Scholar 

  36. Carrassa L, Damia G (2011) Unleashing Chk1 in cancer therapy. Cell Cycle 10:2121–2128

    PubMed  CAS  Google Scholar 

  37. Carrassa L, Sanchez Y, Erba E, Damia G (2009) U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpoint. J Cell Mol Med 13:1565–1576

    PubMed  CAS  Google Scholar 

  38. Lam MH, Liu Q, Elledge SJ, Rosen JM (2004) Chk1 is haploinsufficient for multiple functions critical to tumor suppression. Cancer Cell 6:45–59

    PubMed  CAS  Google Scholar 

  39. Petermann E, Woodcock M, Helleday T (2010) Chk1 promotes replication fork progression by controlling replication initiation. Proc Natl Acad Sci USA 107:16090–16095

    PubMed  CAS  Google Scholar 

  40. Maya-Mendoza A (2007) Chk1 regulates the density of active replication origins during the vertebrate S phase. EMBO Rep 26(11):2719–2731

    CAS  Google Scholar 

  41. Kramer A, Mailand N, Lukas C, Syljuasen RG, Wilkinson CJ, Nigg EA, Bartek J, Lukas J (2004) Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat Cell Biol 6:884–891

    PubMed  Google Scholar 

  42. Zachos G, Black EJ, Walker M, Scott MT, Vagnarelli P, Earnshaw WC, Gillespie DA (2007) Chk1 is required for spindle checkpoint function. Dev Cell 12:247–260

    PubMed  CAS  Google Scholar 

  43. Peddibhotla S, Lam MH, Gonzalez-Rimbau M, Rosen JM (2009) The DNA-damage effector checkpoint kinase 1 is essential for chromosome segregation and cytokinesis. Proc Natl Acad Sci USA 106:5159–5164

    PubMed  CAS  Google Scholar 

  44. Guervilly JH, Mace-Aime G, Rosselli F (2008) Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia. Hum Mol Genet 17:679–689

    PubMed  CAS  Google Scholar 

  45. Tapia-Alveal C, Calonge TM, O’Connell MJ (2009) Regulation of chk1. Cell Div 4:8

    PubMed  Google Scholar 

  46. Zhao H, Piwnica-Worms H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21:4129–4139

    PubMed  CAS  Google Scholar 

  47. Blasius M, Forment JV, Thakkar N, Wagner SA, Choudhary C, Jackson SP (2011) A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol 12:R78

    PubMed  CAS  Google Scholar 

  48. Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell 28:739–745

    PubMed  CAS  Google Scholar 

  49. Chen Y, Poon RY (2008) The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability. Front Biosci 13:5016–5029

    PubMed  CAS  Google Scholar 

  50. Donzelli M, Draetta GF (2003) Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep 4:671–677

    PubMed  CAS  Google Scholar 

  51. Uto K, Inoue D, Shimuta K, Nakajo N, Sagata N (2004) Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism. EMBO J 23:3386–3396

    PubMed  CAS  Google Scholar 

  52. 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 277:1497–1501

    PubMed  CAS  Google Scholar 

  53. Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M, Bartek J, Lukas J (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science 288:1425–1429

    PubMed  CAS  Google Scholar 

  54. Melixetian M, Klein DK, Sorensen CS, Helin K (2009) NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint. Nat Cell Biol 11:1247–1253

    PubMed  CAS  Google Scholar 

  55. O’Connell MJ, Raleigh JM, Verkade HM, Nurse P (1997) Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J 16:545–554

    PubMed  Google Scholar 

  56. Lee J, Kumagai A, Dunphy WG (2001) Positive regulation of Wee1 by Chk1 and 14–3-3 proteins. Mol Biol Cell 12:551–563

    PubMed  CAS  Google Scholar 

  57. Tang J, Erikson RL, Liu X (2006) Checkpoint kinase 1 (Chk1) is required for mitotic progression through negative regulation of polo-like kinase 1 (Plk1). Proc Natl Acad Sci USA 103:11964–11969

    PubMed  CAS  Google Scholar 

  58. Shimada M, Niida H, Zineldeen DH, Tagami H, Tanaka M, Saito H, Nakanishi M (2008) Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 132:221–232

    PubMed  CAS  Google Scholar 

  59. Liu P, Barkley LR, Day T, Bi X, Slater DM, Alexandrow MG, Nasheuer HP, Vaziri C (2006) The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem 281:30631–30644

    PubMed  CAS  Google Scholar 

  60. Yang XH, Shiotani B, Classon M, Zou L (2008) Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev 22:1147–1152

    PubMed  CAS  Google Scholar 

  61. Kannouche PL, Wing J, Lehmann AR (2004) Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell 14:491–500

    PubMed  CAS  Google Scholar 

  62. Freudenthal BD, Gakhar L, Ramaswamy S, Washington MT (2010) Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNA polymerase exchange. Nat Struct Mol Biol 17:479–484

    PubMed  CAS  Google Scholar 

  63. Prakash S, Johnson RE, Prakash L (2005) Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem 74:317–353

    PubMed  CAS  Google Scholar 

  64. Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D’Andrea AD (2007) Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol 27:3098–3108

    PubMed  CAS  Google Scholar 

  65. Sorensen CS, Hansen LT, Dziegielewski J, Syljuasen RG, Lundin C, Bartek J, Helleday T (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 7:195–201

    PubMed  CAS  Google Scholar 

  66. Groth A, Lukas J, Nigg EA, Sillje HH, Wernstedt C, Bartek J, Hansen K (2003) Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J 22:1676–1687

    PubMed  CAS  Google Scholar 

  67. Gonzalez S, Prives C, Cordon-Cardo C (2003) p73 alpha regulation by Chk1 in response to DNA damage. Mol Cell Biol 23:8161–8171

    PubMed  CAS  Google Scholar 

  68. Urist M, Tanaka T, Poyurovsky MV, Prives C (2004) p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev 18:3041–3054

    PubMed  CAS  Google Scholar 

  69. Myers K, Gagou ME, Zuazua-Villar P, Rodriguez R, Meuth M (2009) ATR and Chk1 suppress a caspase-3-dependent apoptotic response following DNA replication stress. PLoS Genet 5:e1000324

    PubMed  Google Scholar 

  70. Sidi S, Sanda T, Kennedy RD, Hagen AT, Jette CA, Hoffmans R, Pascual J, Imamura S, Kishi S, Amatruda JF, Kanki JP, Green DR, D’Andrea AA, Look AT (2008) Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 133:864–877

    PubMed  CAS  Google Scholar 

  71. Katsuragi Y, Sagata N (2004) Regulation of Chk1 kinase by autoinhibition and ATR-mediated phosphorylation. Mol Biol Cell 15:1680–1689

    PubMed  CAS  Google Scholar 

  72. Capasso H, Palermo C, Wan S, Rao H, John UP, O’Connell MJ, Walworth NC (2002) Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle arrest. J Cell Sci 115:4555–4564

    PubMed  CAS  Google Scholar 

  73. Chen P, Luo C, Deng Y, Ryan K, Register J, Margosiak S, Tempczyk-Russell A, Nguyen B, Myers P, Lundgren K, Kan CC, O’Connor PM (2000) The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Cell 100:681–692

    PubMed  CAS  Google Scholar 

  74. Shann YJ, Hsu MT (2001) Cloning and characterization of liver-specific isoform of Chk1 gene from rat. J Biol Chem 276:48863–48870

    PubMed  CAS  Google Scholar 

  75. Kosoy A, O’Connell MJ (2008) Regulation of Chk1 by its C-terminal domain. Mol Biol Cell 19:4546–4553

    PubMed  CAS  Google Scholar 

  76. Okita N, Minato S, Ohmi E, Tanuma S, Higami Y (2012) DNA damage-induced CHK1 autophosphorylation at Ser296 is regulated by an intramolecular mechanism. FEBS Lett 586:3974–3979

    PubMed  CAS  Google Scholar 

  77. Kasahara K, Goto H, Enomoto M, Tomono Y, Kiyono T, Inagaki M (2010) 14–3-3gamma mediates Cdc25A proteolysis to block premature mitotic entry after DNA damage. EMBO J 29:2802–2812

    PubMed  CAS  Google Scholar 

  78. Walker M, Black EJ, Oehler V, Gillespie DA, Scott MT (2009) Chk1 C-terminal regulatory phosphorylation mediates checkpoint activation by de-repression of Chk1 catalytic activity. Oncogene 28:2314–2323

    PubMed  CAS  Google Scholar 

  79. Rodriguez-Bravo V, Guaita-Esteruelas S, Florensa R, Bachs O, Agell N (2006) Chk1- and claspin-dependent but ATR/ATM- and Rad17-independent DNA replication checkpoint response in HeLa cells. Cancer Res 66:8672–8679

    PubMed  CAS  Google Scholar 

  80. Pabla N, Bhatt K, Dong Z (2011) Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints. Proc Natl Acad Sci 109:197–202

    PubMed  Google Scholar 

  81. Zhang YW, Otterness DM, Chiang GG, Xie W, Liu YC, Mercurio F, Abraham RT (2005) Genotoxic stress targets human Chk1 for degradation by the ubiquitin-proteasome pathway. Mol Cell 19:607–618

    PubMed  CAS  Google Scholar 

  82. Zhang YW, Brognard J, Coughlin C, You Z, Dolled-Filhart M, Aslanian A, Manning G, Abraham RT, Hunter T (2009) The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress. Mol Cell 35:442–453

    PubMed  Google Scholar 

  83. Hutchins JR, Hughes M, Clarke PR (2000) Substrate specificity determinants of the checkpoint protein kinase Chk1. FEBS Lett 466:91–95

    PubMed  CAS  Google Scholar 

  84. Bertoni F, Codegoni AM, Furlan D, Tibiletti MG, Capella C, Broggini M (1999) CHK1 frameshift mutations in genetically unstable colorectal and endometrial cancers. Gene Chromosome Canc 26:176–180

    CAS  Google Scholar 

  85. Menoyo A (2001) Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. Cancer Res 61(21):7727–7730

    PubMed  CAS  Google Scholar 

  86. Codegoni AM, Bertoni F, Colella G, Caspani G, Grassi L, D’Incalci M, Broggini M (1999) Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. Oncol Res 11:297–301

    PubMed  CAS  Google Scholar 

  87. Vassileva V (2002) Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability. Cancer Res 62(14):4095–4099

    PubMed  CAS  Google Scholar 

  88. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Canc Cell 3:421–429

    CAS  Google Scholar 

  89. Fishler T, Li YY, Wang RH, Kim HS, Sengupta K, Vassilopoulos A, Lahusen T, Xu X, Lee MH, Liu Q, Elledge SJ, Ried T, Deng CX (2010) Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53. Oncogene 29:4007–4017

    PubMed  CAS  Google Scholar 

  90. Tho LM, Libertini S, Rampling R, Sansom O, Gillespie DA (2012) Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis. Oncogene 31:1366–1375

    PubMed  CAS  Google Scholar 

  91. Verlinden L, Vanden Bempt I, Eelen G, Drijkoningen M, Verlinden I, Marchal K, De Wolf-Peeters C, Christiaens MR, Michiels L, Bouillon R, Verstuyf A (2007) The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor/progesterone receptor/HER-2 breast carcinomas. Cancer Res 67:6574–6581

    PubMed  CAS  Google Scholar 

  92. Zhou BB, Anderson HJ, Roberge M (2003) Targeting DNA checkpoint kinases in cancer therapy. Cancer Biol Ther 2:S16–S22

    PubMed  CAS  Google Scholar 

  93. Zhou BB, Bartek J (2004) Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4:216–225

    PubMed  CAS  Google Scholar 

  94. Lieberman HB (2008) DNA damage repair and response proteins as targets for cancer therapy. Curr Med Chem 15:360–367

    PubMed  CAS  Google Scholar 

  95. Tenzer A, Pruschy M (2003) Potentiation of DNA-damage-induced cytotoxicity by G2 checkpoint abrogators. Curr Med Chem Anticancer Agents 3:35–46

    PubMed  CAS  Google Scholar 

  96. Koniaras K (2001) Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene 20(51):7453–7463

    PubMed  CAS  Google Scholar 

  97. Zenvirt S, Kravchenko-Balasha N, Levitzki A (2010) Status of p53 in human cancer cells does not predict efficacy of CHK1 kinase inhibitors combined with chemotherapeutic agents. Oncogene 29:6149–6159

    PubMed  CAS  Google Scholar 

  98. Blagosklonny MV (2002) Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs. Oncogene 21:6249–6254

    PubMed  CAS  Google Scholar 

  99. Xiao Z, Xue J, Semizarov D, Sowin TJ, Rosenberg SH, Zhang H (2005) Novel indication for cancer therapy: Chk1 inhibition sensitizes tumor cells to antimitotics. Int J Cancer 115:528–538

    PubMed  CAS  Google Scholar 

  100. Arlander SJ, Eapen AK, Vroman BT, McDonald RJ, Toft DO, Karnitz LM (2003) Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. J Biol Chem 278:52572–52577

    PubMed  CAS  Google Scholar 

  101. Guertin AD, Martin MM, Roberts B, Hurd M, Qu X, Miselis NR, Liu Y, Li J, Feldman I, Benita Y, Bloecher A, Toniatti C, Shumway SD (2012) Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer cell Int 12:45

    PubMed  CAS  Google Scholar 

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  1. Navjotsingh Pabla

    Present address: Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee, USA

Authors and Affiliations

  1. Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd., Augusta, GA, 30912, USA

    Mallikarjun Patil, Navjotsingh Pabla & Zheng Dong

  2. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410022, Hunan, China

    Zheng Dong

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  1. Mallikarjun Patil
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Correspondence to Zheng Dong.

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Patil, M., Pabla, N. & Dong, Z. Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell. Mol. Life Sci. 70, 4009–4021 (2013). https://doi.org/10.1007/s00018-013-1307-3

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