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BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.

Original publication

DOI

10.1016/j.molcel.2015.12.017

Type

Journal article

Journal

Mol Cell

Publication Date

04/02/2016

Volume

61

Pages

434 - 448

Keywords

Amino Acid Sequence, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Bone Neoplasms, Carrier Proteins, Cell Line, Tumor, Cell Nucleus, Crystallography, X-Ray, DNA Damage, Germ-Line Mutation, Humans, Models, Molecular, Molecular Sequence Data, Osteosarcoma, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Protein Multimerization, RNA Interference, Serine, Transfection