Structure of BRCA1-BRCT/Abraxas complex reveals phosphorylation-dependent BRCT dimerization at DNA damage sites

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

Authors: Qian Wu (University of Cambridge) , Atanu Paul (The University of Texas MD Anderson Cancer Center) , Dan Su (The University of Texas MD Anderson Cancer Center) , Shahid Mehmood (University of Oxford) , Tzeh keong Foo (Rutgers Cancer Institute of New Jersey) , Takashi Ochi (University of Cambridge) , Emma l. Bunting (University of Cambridge) , Bing Xia (Rutgers Cancer Institute of New Jersey) , Carol v Robinson (University of Oxford) , Bin Wang (The University of Texas MD Anderson Cancer Center) , Tom l. Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: January 2016

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.

Diamond Keywords: Breast Cancer; Ovarian Cancer

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/01/2016 13:05

Documents:
PIIS1097276515009739.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)