Germline RBBP8 variants associated with early-onset breast cancer 1 compromise replication fork stability

Research output: Contribution to journalArticle

Authors

  • Reihaneh Zarrizi
  • Karolin Voßgröne
  • Maria Rossing
  • Birgitte Bertelsen
  • Muthiah Bose
  • Arne Nedergaard Kousholt
  • Heike Rösner
  • The Complexo Network
  • Bent Ejlertsen
  • Finn Cilius Nielsen
  • Claus Sørensen

Colleges, School and Institutes

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. 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) that mediates HR repair through the end-resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants, although 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 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.

Details

Original languageEnglish
JournalJournal of Clinical Investigation
Early online date7 May 2020
Publication statusE-pub ahead of print - 7 May 2020