CHK2-dependent phosphorylation of BRCA1 in hypoxia.
Hypoxia induces a diverse spectrum of changes in the expression and activity of numerous DNA repair factors within the tumor microenvironment. In particular, we and others have shown that hypoxia induces phosphorylation and activation of the checkpoint kinase, CHK2, in an ATM-dependent manner. One downstream target of CHK2, the BRCA1 protein, plays a critical role in both DNA repair and cell cycle checkpoint regulation in mammalian cells. Here we report that BRCA1 is specifically phosphorylated on Serine 988 in response to hypoxic stress, and phosphorylation at this site is dependent on CHK2 expression. These findings enhance our understanding of ATM-CHK2 pathway activation in hypoxia, and they identify a novel role for BRCA1 in the response to hypoxic stress.
Gibson
Shannon L
SL
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-8040, USA.
Bindra
Ranjit S
RS
Glazer
Peter M
PM
D019313:BRCA1 Protein / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology* / Q000528:radiation effects*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011829:Radiation Dosage
D019313:BRCA1 Protein; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases