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

Densham, Ruth M, Garvin, Alexander J, Stone, Helen R, Strachan, Joanna, Baldock, Robert A, Daza-Martin, Manuel, Fletcher, Alice, Blair-Reed, 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 counters chromatin barriers to DNA resection. Nature Structural and Molecular Biology, 23. pp. 647-655. ISSN 1545-9993

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The opposing activities of 53BP1 and BRCA1 influence pathway choice of DNA double-strand break repair. How BRCA1 counters 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. We demonstrate that BRCA1-BARD1’s ubiquitin ligase activity is required for repositioning 53BP1 on damaged chromatin. We confirm H2A ubiquitylation by BRCA1-BARD1 and show that an H2A-ubiquitin fusion protein promotes DNA resection and repair in BARD1 deficient cells. We show BRCA1-BARD1 function in homologous recombination requires the chromatin remodeler SMARCAD1. SMARCAD1 binding to H2A-ubiquitin, 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
Keywords: Accession codes, References, Author information, Supplementary information
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Felicity Watts
Date Deposited: 13 May 2016 09:22
Last Modified: 06 Mar 2017 20:10

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