A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein.
BRCA1 is a central component of the DNA damage response mechanism and defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents. BRCA1 is required for homologous recombination and DNA damage-induced S and G(2)/M phase arrest. We show here that BRCA1 is required for ATM- and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to ionizing or ultraviolet radiation, respectively, and is also required for ATM phosphorylation of CtIP. In contrast, DNA damage-induced phosphorylation of the histone variant H2AX is independent of BRCA1. We also show that the presence of BRCA1 is dispensable for DNA damage-induced phosphorylation of Rad9, Hus1 and Rad17, and for the relocalization of Rad9 and Hus1. We propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA-associated ATM and ATR substrates.
Foray
Nicolas
N
Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
Marot
Didier
D
Gabriel
Anastasia
A
Randrianarison
Voahangy
V
Carr
Antony M
AM
Perricaudet
Michel
M
Ashworth
Alan
A
Jeggo
Penny
P
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D019398:Genes, BRCA1; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C113575:Rad17 protein, human; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; C106332:hus1 protein, S pombe; C069930:rad9 protein; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases