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.
Original language | English |
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Pages (from-to) | 4341-4362 |
Number of pages | 22 |
Journal | Nucleic Acids Research |
Volume | 51 |
Issue number | 9 |
Early online date | 17 Mar 2023 |
DOIs | |
Publication status | Published - 22 May 2023 |
Bibliographical note
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 [email protected].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.
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