Report

DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2

Science  10 Mar 2000:
Vol. 287, Issue 5459, pp. 1824-1827
DOI: 10.1126/science.287.5459.1824

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Abstract

Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2−/− embryonic stem cells failed to maintain γ-irradiation–induced arrest in the G2 phase of the cell cycle. Chk2−/−thymocytes were resistant to DNA damage–induced apoptosis. Chk2−/− cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to γ irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to γ irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. This provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.

  • * Present address: Department of Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.

  • To whom correspondence should be addressed. E-mail: tmak{at}oci.utoronto.ca

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