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Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3.

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.

Pubmed ID: 18510930


  • 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



Publication Data

May 30, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI47891
  • Agency: NHLBI NIH HHS, Id: HL-88664
  • Agency: NHLBI NIH HHS, Id: R01 HL088664
  • Agency: NHLBI NIH HHS, Id: R01 HL088664-02

Mesh Terms

  • Animals
  • Apoptosis
  • Caspase 2
  • Caspase 3
  • Cell Line, Tumor
  • DNA Damage
  • Embryo, Nonmammalian
  • Enzyme Inhibitors
  • Gamma Rays
  • Humans
  • Protein Kinases
  • Proto-Oncogene Proteins c-bcl-2
  • Signal Transduction
  • Tumor Suppressor Protein p53
  • Zebrafish
  • Zebrafish Proteins