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Science 313 (5790): 1122-1126

Copyright © 2006 by the American Association for the Advancement of Science

ATM Engages Autodegradation of the E3 Ubiquitin Ligase COP1 After DNA Damage

David Dornan,1 Harumi Shimizu,1 Angie Mah,1 Tanay Dudhela,1 Michael Eby,2 Karen O'Rourke,1 Somasekar Seshagiri,2 Vishva M. Dixit1*

Abstract: The ataxia telangiectasia mutated (ATM) protein kinase is a critical component of a DNA-damage response network configured to maintain genomic integrity. The abundance of an essential downstream effecter of this pathway, the tumor suppressor protein p53, is tightly regulated by controlled degradation through COP1 and other E3 ubiquitin ligases, such as MDM2 and Pirh2; however, the signal transduction pathway that regulates the COP1-p53 axis following DNA damage remains enigmatic. We observed that in response to DNA damage, ATM phosphorylated COP1 on Ser387 and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on Ser387 was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on Ser387 was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage.

1 Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2 Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

* To whom correspondence should be addressed. E-mail: dixit{at}gene.com

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