BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.
BRCA1/BARD1
DNA repair
chromatin
intrinsically disordered region
ubiquitin
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 08 2023
01 08 2023
Historique:
revised:
10
04
2023
received:
19
01
2023
accepted:
22
05
2023
pmc-release:
12
06
2024
medline:
3
8
2023
pubmed:
12
6
2023
entrez:
12
6
2023
Statut:
ppublish
Résumé
BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.
Identifiants
pubmed: 37305927
doi: 10.15252/embj.2023113565
pmc: PMC10390874
doi:
Substances chimiques
Nucleosomes
0
Tumor Suppressor Proteins
0
BRCA1 Protein
0
Histones
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Chromatin
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
e113565Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM141091
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260834
Pays : United States
Organisme : NICHD NIH HHS
ID : R00 HD090201
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103533
Pays : United States
Informations de copyright
© 2023 The Authors.
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