Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

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

doi:10.1093/nar/gkad172

Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

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 HakemGrant S Stewart, Razqallah Hakem

Research output: Contribution to journal › Article › peer-review

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
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	https://doi.org/10.1093/nar/gkad172
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 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.

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

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10.1093/nar/gkad172Licence: CC BY-NC 4.0

PS Patel et al_Excessive transcription-replication conflicts vulnerability BRCA1-mutant cancers
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
Final published version, 4.54 MBLicence: CC BY-NC 4.0

Cite this

Patel, P. S., Algouneh, A., Krishnan, R., Reynolds, J. J., Nixon, K. C. J., Hao, J., Lee, J., Feng, Y., Fozil, C., Stanic, M., Yerlici, T., Su, P., Soares, F., Liedtke, E., Prive, G., Baider, G. D., Pujana, M. A., Mekhail, K., He, H. H., ... Hakem, R. (2023). Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers. Nucleic Acids Research, 51(9), 4341-4362. https://doi.org/10.1093/nar/gkad172

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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.",

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note = "Copyright {\textcopyright} 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.",

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Patel, PS, Algouneh, A, Krishnan, R, Reynolds, JJ, Nixon, KCJ, Hao, J, Lee, J, Feng, Y, Fozil, C, Stanic, M, Yerlici, T, Su, P, Soares, F, Liedtke, E, Prive, G, Baider, GD, Pujana, MA, Mekhail, K, He, HH, Hakem, A, Stewart, GS & Hakem, R 2023, 'Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers', Nucleic Acids Research, vol. 51, no. 9, pp. 4341-4362. https://doi.org/10.1093/nar/gkad172

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T1 - Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

AU - Patel, Parasvi S

AU - Algouneh, Arash

AU - Krishnan, Rehna

AU - Reynolds, John J

AU - Nixon, Kevin C J

AU - Hao, Jun

AU - Lee, Jihoon

AU - Feng, Yue

AU - Fozil, Chehronai

AU - Stanic, Mia

AU - Yerlici, Talya

AU - Su, Peiran

AU - Soares, Fraser

AU - Liedtke, Elisabeth

AU - Prive, Gil

AU - Baider, Gary D

AU - Pujana, Miquel Angel

AU - Mekhail, Karim

AU - He, Housheng Hansen

AU - Hakem, Anne

AU - Stewart, Grant S

AU - Hakem, Razqallah

N1 - 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.

PY - 2023/5/22

Y1 - 2023/5/22

N2 - 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.

AB - 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.

KW - Humans

KW - BRCA1 Protein/deficiency

KW - DNA Replication/genetics

KW - Hereditary Breast and Ovarian Cancer Syndrome/genetics

KW - Mutation

KW - RNA Polymerase II/metabolism

KW - Transcription, Genetic/genetics

KW - Promoter Regions, Genetic

KW - Methyltransferases/deficiency

KW - R-Loop Structures

KW - Cell Death

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U2 - 10.1093/nar/gkad172

DO - 10.1093/nar/gkad172

M3 - Article

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SN - 0305-1048

VL - 51

SP - 4341

EP - 4362

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 9

ER -

Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

Abstract

Bibliographical note

Keywords

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