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

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journal contribution
posted on 2023-06-09, 01:13 authored by Ruth M Densham, Alexander J Garvin, Helen R Stone, Joanna Strachan, Robert A Baldock, Manuel Daza-Martin, Alice Fletcher, Sarah Blair-Reed, James Beesley, Balraj Johal, Laurence PearlLaurence Pearl, Robert Neely, Nicholas H Keep, Felicity Watts, Joanna R Morris
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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Nature Structural and Molecular Biology

ISSN

1545-9993

Publisher

Nature Publishing Group

Issue

7

Volume

23

Page range

647-655

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-05-13

First Open Access (FOA) Date

2016-11-30

First Compliant Deposit (FCD) Date

2016-05-13

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