Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability.
Cell Biology
Genetic instability
Genetics
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 08 2020
03 08 2020
Historique:
received:
17
01
2019
accepted:
22
04
2020
pubmed:
8
5
2020
medline:
3
2
2021
entrez:
8
5
2020
Statut:
ppublish
Résumé
Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.
Identifiants
pubmed: 32379725
pii: 127521
doi: 10.1172/JCI127521
pmc: PMC7410048
doi:
pii:
Substances chimiques
DNA, Neoplasm
0
Neoplasm Proteins
0
Endodeoxyribonucleases
EC 3.1.-
RBBP8 protein, human
EC 3.1.-
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4069-4080Subventions
Organisme : Medical Research Council
ID : MR/P009085/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C17183/A23303
Pays : United Kingdom
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