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

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

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

  1. Atsushi Hirao1,
  2. Young-Yun Kong1,
  3. Shuhei Matsuoka2,
  4. Andrew Wakeham1,
  5. Jürgen Ruland1,
  6. Hiroki Yoshida1,*,
  7. Dou Liu2,
  8. Stephen J. Elledge2,
  9. Tak W. Mak1,
  1. 1 The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario, M5G 2C1, Canada.
  2. 2 Howard Hughes Medical Institute, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, and Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

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

  • Received for publication 23 November 1999.
  • Accepted for publication 18 January 2000.

Citation:

A. Hirao, Y.-Y. Kong, S. Matsuoka, A. Wakeham, J. Ruland, H. Yoshida, D. Liu, S. J. Elledge, and T. W. Mak, DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2. Science 287, 1824-1827 (2000).

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