Valosin-containing protein phosphorylation at Ser784 in response to DNA damage

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 o...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-09, Vol.65 (17), p.7533-7540
Main Authors: LIVINGSTONE, Mark, HONG RUAN, MOCHAN, Tamara A, DITULLIO, Richard A, MORAVCEVIC, Katarina, GORGOULIS, Vassilis G, BURKHARDT, Anne, HALAZONETIS, Thanos D, WEINER, Jessica, CLAUSER, Karl R, STRACK, Peter, SHENGFANG JIN, WILLIAMS, Amy, GREULICH, Heidi, GARDNER, James, VENERE, Monica
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases
Amino Acid Sequence
Antibodies - pharmacology
Biological and medical sciences
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cell physiology
Checkpoint Kinase 2
DNA Damage - physiology
DNA, Neoplasm - metabolism
Fundamental and applied biological sciences. Psychology
HeLa Cells
Humans
Miscellaneous
Molecular and cellular biology
Molecular Sequence Data
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - immunology
Protein-Serine-Threonine Kinases - metabolism
Serine - metabolism
Transfection
Valosin Containing Protein
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-3729