Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.
BRCA1 encodes a familial breast cancer suppressor that has a critical role in cellular responses to DNA damage. Mouse cells deficient for Brca1 show genetic instability, defective G2-M checkpoint control and reduced homologous recombination. BRCA1 also directly interacts with proteins of the DNA repair machinery and regulates expression of both the p21 and GADD45 genes. However, it remains unclear how DNA damage signals are transmitted to modulate the repair function of BRCA1. Here we show that the BRCA1-associated protein CtIP becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia. ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.
Li
S
S
Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 78245, USA.
Ting
N S
NS
Zheng
L
L
Chen
P L
PL
Ziv
Y
Y
Shiloh
Y
Y
Lee
E Y
EY
Lee
W H
WH
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008741:Methyl Methanesulfonate; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D047908:Intracellular Signaling Peptides and Proteins; D008741:Methyl Methanesulfonate; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C576324:ATM protein, human; C576325:Atm protein, mouse; C410741:RBBP8 protein, human