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. 2023 Oct 19;83(20):3679-3691.e8.
doi: 10.1016/j.molcel.2023.09.015. Epub 2023 Oct 4.

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

Meiling Wang  1 , Wenjing Li  1 , Nozomi Tomimatsu  2 , Corey H Yu  1 , Jae-Hoon Ji  3 , Salvador Alejo  4 , Samuel R Witus  5 , Dauren Alimbetov  1 , O'Taveon Fitzgerald  1 , Bo Wu  1 , Qijing Wang  1 , Yuxin Huang  1 , Yaqi Gan  1 , Felix Dong  1 , Youngho Kwon  1 , Gangadhara R Sareddy  6 , Tyler J Curiel  7 , Amyn A Habib  8 , Robert Hromas  9 , Carolina Dos Santos Passos  10 , Tingting Yao  10 , Dmitri N Ivanov  1 , Peter S Brzovic  5 , Sandeep Burma  11 , Rachel E Klevit  12 , Weixing Zhao  13
Affiliations

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair

Meiling Wang et al. Mol Cell. .

Abstract

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

Keywords: BARD1; BRCA1; DNA damage response; DNA end resection; HDR; histone; homology-directed repair; later stages for HDR completion; substrates; tumor suppression; ubiquitin E3 ligase.

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Conflict of interest statement

Declaration of interests D.N.I. is a co-founder and a shareholder of E3 Bioscience LLC, a commercial entity that manufactures FRET-active E2∼Ub conjugates used in this study.

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