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

Densham, RM; Garvin, AJ; Stone, HR; Strachan, J; Baldock, RA; Daza-Martin, M; Fletcher, A; ... Morris, JR; + view all (2016) Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nature Structural & Molecular Biology , 23 (7) pp. 647-655. 10.1038/nsmb.3236. Green open access

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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.

Type: Article
Title: Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nsmb.3236
Publisher version: https://doi.org/10.1038/nsmb.3236
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Double-strand DNA breaks, Homologous recombination, Tumour-suppressor proteins, Ubiquitylation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10097008
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