BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation.
Abstract
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.
Type
Journal articleSubject
Hela CellsAnimals
Humans
Mice
DNA Damage
RNA Polymerase II
Cell Cycle Proteins
Transcription Factors
S Phase
DNA Replication
Structure-Activity Relationship
HEK293 Cells
Proteolysis
Transcription Elongation, Genetic
Protein Domains
Loss of Function Mutation
R-Loop Structures
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https://hdl.handle.net/10161/24178Published Version (Please cite this version)
10.1016/j.celrep.2020.108166Publication Info
Edwards, Drake S; Maganti, Rohin; Tanksley, Jarred P; Luo, Jie; Park, James JH; Balkanska-Sinclair,
Elena; ... Floyd, Scott R (2020). BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring
Efficient Transcription Elongation. Cell reports, 32(12). pp. 108166. 10.1016/j.celrep.2020.108166. Retrieved from https://hdl.handle.net/10161/24178.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Scott Richard Floyd
Gary Hock and Lyn Proctor Associate Professor of Radiation Oncology

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