Patel, Parasvi S, Algouneh, Arash, Krishnan, Rehna, Reynolds, John J, Nixon, Kevin C J, Hao, Jun, Lee, Jihoon, Feng, Yue, Fozil, Chehronai, Stanic, Mia, Yerlici, Talya, Su, Peiran, Soares, Fraser, Liedtke, Elisabeth, Prive, Gil, Baider, Gary D, Pujana, Miquel Angel, Mekhail, Karim, He, Housheng Hansen, Hakem, Anne, Stewart, Grant S and Hakem, Razqallah (2023). Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers. Nucleic Acids Research, 51 (9), pp. 4341-4362.
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.
Publication DOI: | https://doi.org/10.1093/nar/gkad172 |
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Divisions: | College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences Aston University (General) |
Additional Information: | Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com. Funding acknowledged: Lee K. and Margaret Lau Chair in Breast Cancer Research, a joint project with the University of Toronto and the Princess Margaret Hospital (to R.H.); STARS21, Terry Fox Foundation; Princess Margaret Cancer Foundation; Department of Medical Biophysics, University of Toronto; Ontario Graduate Scholarship, Government of Ontario (to P.S.P.); Canada Graduate Scholarships for Master's program; Ontario Graduate Scholarship; Department of Laboratory Medicine and Pathobiology, University of Toronto (to A.A.); Canadian Institute of Health Research [FDN 143214 to R.H.]; Canadian Cancer Society [705367, 706439 to R.H.]; Canadian Institute of Health Research and Cancer Research Society [24418 to R.H.]; Cancer Research UK program [C17183/A23303 to G.S.S.]; University of Birmingham (to J.J.R.); Canadian Institute of Health Research CIHR [PJT-175083 to G.P.]; Samuel Waxman Cancer Research Foundation (to G.P.); Carlos III Institute of Health [PI18/01029] co-funded by European Regional Development Fund (ERDF), a way to build Europe, Generalitat de Catalunya SGR [2017-449]; CERCA Program to IDIBELL (to M.A.P.). Funding for open access charge: CIHR. |
Uncontrolled Keywords: | Humans,BRCA1 Protein/deficiency,DNA Replication/genetics,Hereditary Breast and Ovarian Cancer Syndrome/genetics,Mutation,RNA Polymerase II/metabolism,Transcription, Genetic/genetics,Promoter Regions, Genetic,Methyltransferases/deficiency,R-Loop Structures,Cell Death |
Publication ISSN: | 1362-4962 |
Last Modified: | 02 Dec 2024 08:55 |
Date Deposited: | 20 Jun 2023 14:40 |
Full Text Link: | |
Related URLs: |
https://academi ... /9/4341/7079642
(Publisher URL) http://www.scop ... tnerID=8YFLogxK (Scopus URL) |
PURE Output Type: | Article |
Published Date: | 2023-05-22 |
Published Online Date: | 2023-03-17 |
Accepted Date: | 2023-03-14 |
Authors: |
Patel, Parasvi S
Algouneh, Arash Krishnan, Rehna Reynolds, John J ( 0000-0001-8690-5828) Nixon, Kevin C J Hao, Jun Lee, Jihoon Feng, Yue Fozil, Chehronai Stanic, Mia Yerlici, Talya Su, Peiran Soares, Fraser Liedtke, Elisabeth Prive, Gil Baider, Gary D Pujana, Miquel Angel Mekhail, Karim He, Housheng Hansen Hakem, Anne Stewart, Grant S Hakem, Razqallah |