DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis.
BRCA2 Protein
/ metabolism
Humans
DNA Replication
Homologous Recombination
DNA
/ metabolism
Rad51 Recombinase
/ metabolism
Mutation
DNA, Single-Stranded
/ metabolism
Homeostasis
Protein Binding
DNA-Binding Proteins
/ metabolism
Protein Domains
Cell Line, Tumor
DNA Damage
Proteasome Endopeptidase Complex
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 Aug 2024
17 Aug 2024
Historique:
received:
03
01
2024
accepted:
09
08
2024
medline:
17
8
2024
pubmed:
17
8
2024
entrez:
16
8
2024
Statut:
epublish
Résumé
DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.
Identifiants
pubmed: 39152168
doi: 10.1038/s41467-024-51557-6
pii: 10.1038/s41467-024-51557-6
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
DNA
9007-49-2
Rad51 Recombinase
EC 2.7.7.-
DNA, Single-Stranded
0
SEM1 protein, human
0
DNA-Binding Proteins
0
RAD51 protein, human
EC 2.7.7.-
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7081Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R01GM141091
Organisme : Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
ID : RP210102
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA268641
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA246807
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA138804
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA262227
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA282939
Organisme : American Cancer Society (American Cancer Society, Inc.)
ID : RSG-22-721675-01-DMC
Organisme : V Foundation for Cancer Research (V Foundation)
ID : V scholar Award
Organisme : Max and Minnie Tomerlin Voelcker Fund (Voelcker Fund)
ID : a Young Investigator Award
Informations de copyright
© 2024. The Author(s).
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