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[Cancer Research 65, 7533-7540, September 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Valosin-Containing Protein Phosphorylation at Ser784 in Response to DNA Damage

Mark Livingstone1, Hong Ruan1, Jessica Weiner2, Karl R. Clauser2, Peter Strack2, Shengfang Jin2, Amy Williams2, Heidi Greulich2, James Gardner2, Monica Venere3,4, Tamara A. Mochan3,4, Richard A. DiTullio, Jr.3,4, Katarina Moravcevic3,4, Vassilis G. Gorgoulis3, Anne Burkhardt2 and Thanos D. Halazonetis3,5

1 Cell Signaling Technology, Inc., Beverly, Massachusetts; 2 Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; 3 Wistar Institute; 4 Cell and Molecular Biology and Biochemistry Graduate Groups, Biomedical Graduate Studies; and 5 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Thanos D. Halazonetis, Wistar Institute, Room 115, Philadelphia, PA 19104. Phone: 215-898-3789; Fax: 215-573-9271; E-mail: halazonetis{at}wistar.upenn.edu.

The response of eukaryotic cells to DNA damage includes the activation of phosphatidylinositol-3 kinase–related kinases (PIKK), such as ATM, ATR, and DNA-dependent protein kinase (DNA-PK). These three kinases have very similar substrate specificities in vitro, but in vivo, their substrates overlap only partially. Several in vivo substrates of ATM and ATR have been identified and almost all of them are involved in DNA damage–induced cell cycle arrest and/or apoptosis. In contrast, few in vivo substrates of DNA-PK have been identified. These include histone H2AX and DNA-PK itself. We identify here valosin-containing protein (VCP) as a novel substrate of DNA-PK and other PIKK family members. VCP is phosphorylated at Ser784 within its COOH terminus, a region previously shown to target VCP to specific intracellular compartments. Furthermore, VCP phosphorylated at Ser784 accumulated at sites of DNA double-strand breaks (DSBs). VCP is a protein chaperone that unfolds and translocates proteins. Its phosphorylation in response to DNA damage and its recruitment to sites of DNA DSBs could indicate a role of VCP in DNA repair.




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