Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.
BARD1
BRCA1
DNA damage response
DNA end resection
HDR
histone
homology-directed repair
later stages for HDR completion
substrates
tumor suppression
ubiquitin E3 ligase
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
19 10 2023
19 10 2023
Historique:
received:
21
03
2023
revised:
08
08
2023
accepted:
11
09
2023
pmc-release:
19
10
2024
medline:
26
10
2023
pubmed:
6
10
2023
entrez:
5
10
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37797621
pii: S1097-2765(23)00734-7
doi: 10.1016/j.molcel.2023.09.015
pmc: PMC10591799
mid: NIHMS1932878
pii:
doi:
Substances chimiques
Tumor Suppressor Proteins
0
BRCA1 Protein
0
Histones
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
DNA
9007-49-2
BARD1 protein, human
EC 2.3.2.27
BRCA1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3679-3691.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA246807
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA268641
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA265315
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244212
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260834
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS106173
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM141091
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136697
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
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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