Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 23, Issue 7, Pages 647-655Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3236
Keywords
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Funding
- CRUK [C8820/A19062, C302/A14532, C1206/A11978]
- Breast Cancer Campaign [2010MayPR01, 2013NovPR132]
- Engineering and Physical Sciences Research Council [EP/L016346/1]
- University of Birmingham
- University of Sussex
- HEFCE
- NIH Protein Structure Initiative grant
- Northeast Structural Genomics Consortium
- Cancer Research UK [14532, 19062, 11978] Funding Source: researchfish
- Medical Research Council [1367609] Funding Source: researchfish
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The opposing activities of 53BP1 and BRCA1 influence pathway choice in DNA double-strand-break repair. How BRCA1 counteracts the inhibitory effect of 53BP1 on DNA resection and homologous recombination is unknown. Here we identify the site of BRCA1-BARD1 required for priming ubiquitin transfer from E2 similar to ubiquitin and demonstrate that BRCA1-BARD1's ubiquitin ligase activity is required for repositioning 53BP1 on damaged chromatin. We confirm H2A ubiquitination by BRCA1-BARD1 and show that an H2A-ubiquitin fusion protein promotes DNA resection and repair in BARD1-deficient cells. BRCA1-BARD1's function in homologous recombination requires the chromatin remodeler SMARCAD1. SMARCAD1 binding to H2A-ubiquitin and optimal localization to sites of damage and activity in DNA repair requires its ubiquitin-binding CUE domains. SMARCAD1 is required for 53BP1 repositioning, and the need for SMARCAD1 in olaparib or camptothecin resistance is alleviated by 53BP1 loss. Thus, BRCA1-BARD1 ligase activity and subsequent SMARCAD1-dependent chromatin remodeling are critical regulators of DNA repair.
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