Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers
| العنوان: | Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers |
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| المؤلفون: | Parasvi S Patel, Arash Algouneh, Rehna Krishnan, John J Reynolds, Kevin C J Nixon, Jun Hao, Jihoon Lee, Yue Feng, Chehronai Fozil, Mia Stanic, Talya Yerlici, Peiran Su, Fraser Soares, Elisabeth Liedtke, Gil Prive, Gary D Baider, Miquel Angel Pujana, Karim Mekhail, Housheng Hansen He, Anne Hakem, Grant S Stewart, Razqallah Hakem |
| المصدر: | Nucleic Acids Research. 51:4341-4362 |
| بيانات النشر: | Oxford University Press (OUP), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Genetics |
| الوصف: | 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. |
| تدمد: | 1362-4962 0305-1048 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::4313c9c9d7f68085ba665c9f63f028baTest https://doi.org/10.1093/nar/gkad172Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi...........4313c9c9d7f68085ba665c9f63f028ba |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13624962 03051048 |
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