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Review
. 2025 May 2;39(9-10):539-540.
doi: 10.1101/gad.352827.125.

Gap resection matters in BRCA mutant cancer

Lee Zou  1
Affiliations
Review

Gap resection matters in BRCA mutant cancer

Lee Zou. Genes Dev. .

Abstract

Cancer cells deficient in BRCA1/2 have impaired DNA repair, making them sensitive to PARP inhibitors (PARPis). In this issue of Genes & Development, Seppa and colleagues (doi:10.1101/gad.352421.124) investigated how BRCA1 protects single-stranded DNA gaps from nucleolytic processing. They showed that PARPi-induced gaps are rapidly resected by several exonucleases bidirectionally and filled by translesion synthesis. In BRCA1-deficient cells, gaps become larger and persistent due to excessive resection. These gaps do not convert to DNA double-stranded breaks (DSBs) via endonuclease activity but cause DSBs through replication fork collisions in a cell cycle-dependent manner. This research clarifies how BRCA1 loss contributes to PARPi sensitivity in BRCA mutant tumors.

Keywords: BRCA; DNA replication; DNA replication stress; MRE11; PARP inhibitor; genome stability; nucleases; single-stranded DNA gaps.

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