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

Reihaneh Zarrizi, Martin R Higgs, Karolin Voßgröne, Maria Rossing, Birgitte Bertelsen, Muthiah Bose, Arne Nedergaard Kousholt, Heike Rösner, The Complexo Network, Bent Ejlertsen, Grant S Stewart, Finn Cilius Nielsen, Claus S Sørensen

20 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftThe Journal of clinical investigation
Vol/bind140
Udgave nummer8
Sider (fra-til)4069-4080
Antal sider12
ISSN0021-9738
DOI
StatusUdgivet - 3 aug. 2020

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