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

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.

Automated summary

BRCA1 mutations increase the risk of breast and ovarian cancer. This study identified MEPCE and PAF1 as synthetic lethal partners of BRCA1 by targeting CRISPR-Cas9 screening. Depletion of MEPCE and PAF1 resulted in dysregulated RNAPII promoter-proximal pausing, R-loop accumulation, replication stress, and genomic instability, leading to the loss of viability in BRCA1-deficient cells. These findings suggest that targeting transcription-replication collision-inducing factors could be a potential therapeutic approach for cancers associated with BRCA1 mutations.