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 Hakem

Grant S. Stewart, Razqallah Hakem^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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

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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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Genetics

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10.1093/nar/gkad172Licence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

PatelP2023ExcessiveFinal published version, 4.55 MBLicence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer
Stewart, G. (Principal Investigator)
Cancer Research UK
1/09/17 → 31/05/25
Project: Research

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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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title = "Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers",

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.",

author = "Patel, \{Parasvi S.\} and Arash Algouneh and Rehna Krishnan and Reynolds, \{John J.\} and Nixon, \{Kevin C J\} and Jun Hao and Jihoon Lee and Yue Feng and Chehronai Fozil and Mia Stanic and Talya Yerlici and Peiran Su and Fraser Soares and Elisabeth Liedtke and Gil Prive and Baider, \{Gary D\} and Pujana, \{Miquel Angel\} and Karim Mekhail and He, \{Housheng Hansen\} and Anne Hakem and Stewart, \{Grant S.\} and Razqallah Hakem",

note = "Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.",

year = "2023",

month = may,

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doi = "10.1093/nar/gkad172",

language = "English",

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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

TY - JOUR

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

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.

UR - https://www.scopus.com/pages/publications/85159766954

U2 - 10.1093/nar/gkad172

DO - 10.1093/nar/gkad172

M3 - Article

C2 - 36928661

AN - SCOPUS:85159766954

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

UN SDGs

ASJC Scopus subject areas

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Projects

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer

Cite this