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Nat Struct Mol Biol. 2016 Jul;23(7):647-55. doi: 10.1038/nsmb.3236. Epub 2016 May 30.

Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection.

Author information

1
Birmingham Centre for Genome Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
2
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
3
School of Chemistry, University of Birmingham, Birmingham, UK.
4
Department of Biological Sciences, Institute for Structural and Molecular Biology, Birkbeck, University of London, London, UK.

Abstract

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∼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.

PMID:
27239795
DOI:
10.1038/nsmb.3236
[Indexed for MEDLINE]

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