Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites

Mol Cell. 2016 Feb 4;61(3):434-448. doi: 10.1016/j.molcel.2015.12.017.

Qian Wu ¹, Atanu Paul ², Dan Su ³, Shahid Mehmood ⁴, Tzeh Keong Foo ⁵, Takashi Ochi ¹, Emma L Bunting ¹, Bing Xia ⁵, Carol V Robinson ⁴, Bin Wang ⁶, Tom L Blundell ⁷

Affiliations

1 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK.
2 Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Genes and Development Program, The University of Texas Graduate School of Biomedical Sciences at Houston, 6767 Bertner Avenue, Houston, TX 77030, USA.
3 Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
4 Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
5 Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
6 Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Genes and Development Program, The University of Texas Graduate School of Biomedical Sciences at Houston, 6767 Bertner Avenue, Houston, TX 77030, USA. Electronic address: [email protected].
7 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA Cambridge, UK. Electronic address: [email protected].

PMID: 26778126 DOI: 10.1016/j.molcel.2015.12.017

Abstract

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.

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