title: Valosin-containing protein phosphorylation at Ser784 in response to DNA damage.
abstract: 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.
authors.affiliation: Cell Signaling Technology, Inc., Beverly, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Livingstone
authors.forename: Hong
authors.initials: H
authors.lastname: Ruan
authors.forename: Jessica
authors.initials: J
authors.lastname: Weiner
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.forename: Peter
authors.initials: P
authors.lastname: Strack
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.forename: Amy
authors.initials: A
authors.lastname: Williams
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: James
authors.initials: J
authors.lastname: Gardner
authors.forename: Monica
authors.initials: M
authors.lastname: Venere
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Mochan
authors.forename: Richard A
authors.initials: RA
authors.lastname: DiTullio
authors.forename: Katarina
authors.initials: K
authors.lastname: Moravcevic
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.forename: Anne
authors.initials: A
authors.lastname: Burkhardt
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D000251:Adenosine Triphosphatases; D000595:Amino Acid Sequence; D000906:Antibodies / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology*; D004273:DNA, Neoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014162:Transfection; D000074405:Valosin Containing Protein
chemical_list: D000251:Adenosine Triphosphatases; D000906:Antibodies; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004273:DNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000074405:Valosin Containing Protein; C578634:CHEK2 protein, human; C000614178:VCP protein, human