Research output per year
Research output per year
The COMPLEXO Network
Research output: Contribution to journal › Article › peer-review
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.
Original language | English |
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Pages (from-to) | 4069-4080 |
Number of pages | 12 |
Journal | Journal of Clinical Investigation |
Volume | 130 |
Issue number | 8 |
Early online date | 7 May 2020 |
DOIs | |
Publication status | Published - 3 Aug 2020 |
Research output: Contribution to journal › Article › peer-review
1/04/17 → 31/03/23
Project: Research Councils