Excessive transcription-replication conflicts are a vulnerability of <i>BRCA1</i>-mutant cancers
Parasvi S. Patel, Arash Algouneh, Rehna Krishnan, John J. Reynolds, Kevin C. Nixon, Jun Hao, Jihoon Lee, Yue Feng, Chehronai Fozil, Mia Stanić, Talya Yerlici, Peiran Su, Fraser Soares, Elisabeth Liedtke, Gil Privé, Gary D Baider, Miguel Ángel Pujana, Karim Mekhail, Housheng Hansen He, Anne Hakem, Grant S. Stewart, Razqallah Hakem
Abstract
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.