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

Densham, Ruth M, Garvin, Alexander J, Stone, Helen R, Strachan, Joanna, Baldock, Robert A ORCID: 0000-0002-4649-2966, Daza-Martin, Manuel, Fletcher, Alice, Blair-Reid, Sarah, Beesley, James, Johal, Balraj, Pearl, Laurence H, Neely, Robert, Keep, Nicholas H, Watts, Felicity Z and Morris, Joanna R (2016) Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nature Structural and Molecular Biology, 23 (7). pp. 647-655. doi:10.1038/nsmb.3236

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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.

Item Type:	Article
Article Type:	Article
Additional Information:	This is the accepted version of an article published by Nature Portfolio in July 2016: Densham, R., Garvin, A., Stone, H. et al. Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat Struct Mol Biol 23, 647–655 (2016). https://doi.org/10.1038/nsmb.3236
Related URLs:	Dataset
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH426 Genetics
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Place, Environment and Community
Depositing User:	Robbie Baldock
Date Deposited:	08 Jun 2021 15:33
Last Modified:	10 Apr 2024 14:00
URI:	https://eprints.glos.ac.uk/id/eprint/9780

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