Unknown

Dataset Information

0

Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability.


ABSTRACT: 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.

SUBMITTER: Zarrizi R 

PROVIDER: S-EPMC7410048 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications


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  ...[more]

Similar Datasets

| S-EPMC7749988 | biostudies-literature
| S-EPMC7796867 | biostudies-literature
| S-EPMC2727422 | biostudies-literature
| S-EPMC5949367 | biostudies-literature
| S-EPMC9528965 | biostudies-literature
| S-EPMC10290672 | biostudies-literature
| S-EPMC5369655 | biostudies-literature
| S-EPMC5588928 | biostudies-literature
| S-EPMC8688197 | biostudies-literature
| S-EPMC7526538 | biostudies-literature