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 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.
Livingstone
Mark
M
Cell Signaling Technology, Inc., Beverly, Massachusetts, USA.
Ruan
Hong
H
Weiner
Jessica
J
Clauser
Karl R
KR
Strack
Peter
P
Jin
Shengfang
S
Williams
Amy
A
Greulich
Heidi
H
Gardner
James
J
Venere
Monica
M
Mochan
Tamara A
TA
DiTullio
Richard A
RA
Moravcevic
Katarina
K
Gorgoulis
Vassilis G
VG
Burkhardt
Anne
A
Halazonetis
Thanos D
TD
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
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