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Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers.

Parasvi S PatelArash AlgounehRehna KrishnanJohn J ReynoldsKevin C J NixonJun HaoJihoon LeeYue FengChehronai FozilMia StanicTalya YerliciPeiran SuFraser SoaresElisabeth LiedtkeGil PriveGary D BaiderMiquel Angel PujanaKarim MekhailHousheng Hansen HeAnne HakemGrant S StewartRazqallah Hakem
Published in: Nucleic acids research (2023)
BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.
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