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Molecular and Cellular Biology, October 2008, p. 5874-5885, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00821-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Chk2 Ubiquitination and Signaling through Autophosphorylation of Serine 379{triangledown}

Christine M. Lovly ,1,{dagger},{ddagger} Ling Yan,3,{ddagger} Christine E. Ryan,3 Saeko Takada,1,§ and Helen Piwnica-Worms1,2,3*

Department of Cell Biology and Physiology,1 Department of Internal Medicine,2 Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, Missouri 63110-10933

Received 21 May 2008/ Returned for modification 24 June 2008/ Accepted 10 July 2008

The Chk2 protein kinase protects genome integrity by promoting cell cycle arrest or apoptosis in response to DNA double-strand breaks, and Chk2 mutations are found in both familial and sporadic cancers. Exposure of cells to ionizing radiation (IR) or radiomimetic drugs induces Chk2 phosphorylation by ATM, followed by Chk2 oligomerization, auto-/transphosphorylation, and activation. Here we demonstrate that Chk2 is ubiquitinated upon activation and that this requires Chk2 kinase activity. Serine 379 (S379) was identified as a novel IR-inducible autophosphorylation site required for ubiquitination of Chk2 by a Cullin 1-containing E3 ligase complex. Importantly, S379 was required for Chk2 to induce apoptosis in cells with DNA double-strand breaks. Thus, auto-/transphosphorylation of S379 is required for Chk2 ubiquitination and effector function.

* Corresponding author. Mailing address: Department of Cell Biology and Physiology and Howard Hughes Medical Institute, Washington University School of Medicine, Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-6812. Fax: (314) 362-3709. E-mail: hpiwnica{at}cellbiology.wustl.edu

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Present address: Vanderbilt Department of Medicine Physician-Scientist Training Program, Vanderbilt University, Nashville, TN.

{ddagger} These authors contributed equally.

§ Present address: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN.

Molecular and Cellular Biology, October 2008, p. 5874-5885, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00821-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Xu, Y.-j., Kelly, T. J. (2009). Autoinhibition and Autoactivation of the DNA Replication Checkpoint Kinase Cds1. J. Biol. Chem. 284: 16016-16027 [Abstract] [Full Text]  


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