Requirement of ATM-Dependent Phosphorylation of Brca1 in the DNA Damage Response to Double-Strand Breaks

TLDR

Brca1 is phosphorylated in response to DNA damage. ATM is required for Brca1 phosphorylation after ionizing radiation, forming a complex with Brca1 and phosphorylating a serine‑glutamine cluster; loss of two phosphorylation sites abolishes rescue of radiation hypersensitivity, indicating ATM‑mediated Brca1 phosphorylation is critical for double‑strand break repair and may explain ATM’s role in breast cancer.

Abstract

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.