1. Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78245, USA
2. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

Correspondence to: Wen-Hwa Lee¹ Correspondence and requests for materials should be addressed to W.-H.L. (e-mail: Email: leew@uthscsa.edu).

Abstract

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 show genetic instability, defective G2–M checkpoint control and reduced homologous recombination^{3, 4}. BRCA1 also directly interacts with proteins of the DNA repair machinery⁵ and regulates expression of both the p21 and GADD45 genes^{6, 7, 8}. 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^{9, 10, 11, 12} becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia¹³. 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.