DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

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DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

A A Hirao, Y Y YY Kong, S S Matsuoka, A A Wakeham, J J Ruland, H H Yoshida, D D Liu, S J SJ Elledge and T W TW Mak Science 287(5459):1824-7 (2000) PMID 10710310

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 gamma-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 gamma irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma 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.

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