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(1,2). Mouse cells deficient for Brca1 s how genetic instability, defective G2-M checkpoint control and reduced homo logous recombination(3,4). BRCA1 also directly interacts with proteins of t he DNA repair machinery(5) and regulates expression of both the p21 and GAD D45 genes(6-8). However, it remains unclear how DNA damage signals are tran smitted to modulate the repair function of BRCA1. Here we show that the BRC A1-associated protein CtIP(9-12) becomes hyperphosphorylated and dissociate d from BRCA1 upon ionizing radiation. This phosphorylation event requires t he protein kinase (ATM) that is mutated in the disease ataxia telangiectasi a(13). ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, r esulting in persistent repression of BRCA1-dependent induction of GADD45 up on ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon i onizing radiation, may modulate BRCA1-mediated regulation of the DNA damage -response GADD45 gene, thus providing a potential link between ATM deficien cy and breast cancer.