Conservation of transcriptional regulation by BRCA1 and BARD1 in Caenorhabditis elegans.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 03 2023
21 03 2023
Historique:
accepted:
29
09
2022
revised:
22
09
2022
received:
14
07
2022
pubmed:
18
10
2022
medline:
21
3
2023
entrez:
17
10
2022
Statut:
ppublish
Résumé
The tumor-suppressor proteins BRCA1 and BARD1 function as an E3 ubiquitin ligase to facilitate transcriptional repression and DNA damage repair. This is mediated in-part through its ability to mono-ubiquitylate histone H2A in nucleosomes. Studies in Caenorhabditis elegans have been used to elucidate numerous functions of BRCA1 and BARD1; however, it has not been established that the C. elegans orthologs, BRC-1 and BRD-1, retain all the functions of their human counterparts. Here we explore the conservation of enzymatic activity toward nucleosomes which leads to repression of estrogen-metabolizing cytochrome P450 (cyp) genes in humans. Biochemical assays establish that BRC-1 and BRD-1 contribute to ubiquitylation of histone H2A in the nucleosome. Mutational analysis shows that while BRC-1 likely binds the nucleosome using a conserved interface, BRD-1 and BARD1 have evolved different modes of binding, resulting in a difference in the placement of ubiquitin on H2A. Gene expression analysis reveals that in spite of this difference, BRC-1 and BRD-1 also contribute to cyp gene repression in C. elegans. Establishing conservation of these functions in C. elegans allows for use of this powerful model organism to address remaining questions regarding regulation of gene expression by BRCA1 and BARD1.
Identifiants
pubmed: 36250637
pii: 6761983
doi: 10.1093/nar/gkac877
pmc: PMC10018340
doi:
Substances chimiques
BARD1 protein, human
EC 2.3.2.27
BRCA1 Protein
0
brd-1 protein, C elegans
0
Caenorhabditis elegans Proteins
0
Histones
0
Nucleosomes
0
Tumor Suppressor Proteins
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
BRC-1 protein, C elegans
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
2108-2116Subventions
Organisme : NCI NIH HHS
ID : R01 CA079953
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260834
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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