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

Meiling Wang, Wenjing Li, Nozomi Tomimatsu, Corey H. Yu, Jae Hoon Ji, Salvador Alejo, Samuel R. Witus, Dauren Alimbetov, O'Taveon T. Fitzgerald, Bo Wu, Qijing Wang, Yuxin Huang, Yaqi Gan, Felix Dong, Youngho Kwon, Gangadhara R. Sareddy, Tyler J. Curiel, Amyn A. Habib, Robert Hromas, Carolina dos Santos PassosTingting Yao, Dmitri N. Ivanov, Peter S. Brzovic, Sandeep Burma, Rachel E. Klevit, Weixing Zhao

Producción científica: Articlerevisión exhaustiva

2 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)3679-3691.e8
PublicaciónMolecular Cell
Volumen83
N.º20
DOI
EstadoPublished - oct 19 2023

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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