Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability
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- JCI127521.v3
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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.
Originalsprog | Engelsk |
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Tidsskrift | The Journal of Clinical Investigation |
Vol/bind | 130 |
Udgave nummer | 8 |
Sider (fra-til) | 4069-4080 |
Antal sider | 12 |
ISSN | 0021-9738 |
DOI | |
Status | Udgivet - 3 aug. 2020 |
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