Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks.
The Brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to DNA damage. Results from this study indicate that the checkpoint protein kinase ATM (mutated in ataxia telangiectasia) was required for phosphorylation of Brca1 in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated Brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Thus, phosphorylation of Brca1 by the checkpoint kinase ATM may be critical for proper responses to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer.
Cortez
D
D
Verna and Mars McLean Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Y
Y
Qin
J
J
Elledge
S J
SJ
D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005260:Female; D005720:Gamma Rays; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases