BRCA1基因突变与增加乳腺和卵巢癌风险相关。BRCA1突变肿瘤具有高级别、复发性，并经常变得对标准疗法具有抗药性。在本文中，我们进行了有针对性的CRISPR-Cas9筛选，并确定MEPCE作为BRCA1的合成致死互作物。从机理上讲，我们证明在BRCA1缺失的环境下去除MEPCE会导致RNA聚合酶II（RNAPII）启动子近端停顿、R-loop积累和复制应激，促进转录-复制碰撞。这些碰撞会损害基因组完整性，导致BRCA1缺失细胞的生存能力丧失。我们还将这些发现扩展到另一种RNAPII调控因子PAF1。这项研究确定了BRCA1的新型合成致死伴侣类别，利用RNAPII停顿调控，并强调尚未开发的转录-复制碰撞诱导因子作为治疗与BRCA1基因突变相关癌症的独特潜在治疗靶点的潜力。©本文作者2023年首次发表。牛津大学出版社代表核酸研究出版。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.