Journal
MOLECULAR CELL
Volume 61, Issue 3, Pages 434-448Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.12.017
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Funding
- Wellcome Trust [093167/Z/10/Z]
- Schissler Foundation Fellowship
- Center for Cancer Epigenetics Scholarship
- Andrew Sowell-Wade Huggins Scholarship
- NIH [CA155025, R01CA138804]
- University of Texas MD Anderson Cancer Center (IRG, Center for Cancer Epigenetics, Center for Genetics, and Genomics Pilot Award)
- Medical Research Council [98101]
- Medical Research Council [G1000819] Funding Source: researchfish
- MRC [G1000819] Funding Source: UKRI
- Wellcome Trust [093167/Z/10/Z] Funding Source: Wellcome Trust
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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 Abraxasmediated recruitment of BRCA1 in response to IR.
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