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BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation

Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery, causing DNA damage and cell death. BRD4 allows...

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Autores principales: Edwards, Drake S., Maganti, Rohin, Tanksley, Jarred P., Luo, Jie, Park, James J.H., Balkanska-Sinclair, Elena, Ling, Jinjie, Floyd, Scott R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507985/
https://www.ncbi.nlm.nih.gov/pubmed/32966794
http://dx.doi.org/10.1016/j.celrep.2020.108166
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author Edwards, Drake S.
Maganti, Rohin
Tanksley, Jarred P.
Luo, Jie
Park, James J.H.
Balkanska-Sinclair, Elena
Ling, Jinjie
Floyd, Scott R.
author_facet Edwards, Drake S.
Maganti, Rohin
Tanksley, Jarred P.
Luo, Jie
Park, James J.H.
Balkanska-Sinclair, Elena
Ling, Jinjie
Floyd, Scott R.
author_sort Edwards, Drake S.
collection PubMed
description Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery, causing DNA damage and cell death. BRD4 allows efficient transcriptional elongation by stimulating phosphorylation of RNA polymerase II (RNAPII). We report that bromodomain and extra-terminal domain (BET) protein loss of function (LOF) causes RNAPII pausing on the chromatin and DNA damage affecting cells in S-phase. This persistent RNAPII-dependent pausing leads to an accumulation of RNA:DNA hybrids (R-loops) at sites of BRD4 occupancy, leading to transcription-replication conflicts (TRCs), DNA damage, and cell death. Finally, our data show that the BRD4 C-terminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET protein LOF.
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spelling pubmed-75079852020-09-23 BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation Edwards, Drake S. Maganti, Rohin Tanksley, Jarred P. Luo, Jie Park, James J.H. Balkanska-Sinclair, Elena Ling, Jinjie Floyd, Scott R. Cell Rep Article Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery, causing DNA damage and cell death. BRD4 allows efficient transcriptional elongation by stimulating phosphorylation of RNA polymerase II (RNAPII). We report that bromodomain and extra-terminal domain (BET) protein loss of function (LOF) causes RNAPII pausing on the chromatin and DNA damage affecting cells in S-phase. This persistent RNAPII-dependent pausing leads to an accumulation of RNA:DNA hybrids (R-loops) at sites of BRD4 occupancy, leading to transcription-replication conflicts (TRCs), DNA damage, and cell death. Finally, our data show that the BRD4 C-terminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET protein LOF. The Author(s). 2020-09-22 2020-09-22 /pmc/articles/PMC7507985/ /pubmed/32966794 http://dx.doi.org/10.1016/j.celrep.2020.108166 Text en © 2020 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Edwards, Drake S.
Maganti, Rohin
Tanksley, Jarred P.
Luo, Jie
Park, James J.H.
Balkanska-Sinclair, Elena
Ling, Jinjie
Floyd, Scott R.
BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title_full BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title_fullStr BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title_full_unstemmed BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title_short BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation
title_sort brd4 prevents r-loop formation and transcription-replication conflicts by ensuring efficient transcription elongation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507985/
https://www.ncbi.nlm.nih.gov/pubmed/32966794
http://dx.doi.org/10.1016/j.celrep.2020.108166
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