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 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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Publication Info

Edwards, Drake S, Rohin Maganti, Jarred P Tanksley, Jie Luo, James JH Park, Elena Balkanska-Sinclair, Jinjie Ling, Scott R Floyd, et al. (2020). BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation. Cell reports, 32(12). p. 108166. 10.1016/j.celrep.2020.108166 Retrieved from

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Scott Richard Floyd

Gary Hock and Lyn Proctor Associate Professor of Radiation Oncology

Diseases of the brain carry particular morbidity and mortality, given the fundamental function of the brain for human life and quality of life. Disease of the brain are also particularly difficult to study, given the complexity of the brain. Model systems that capture this complexity, but still allow for experiments to test therapies and mechanisms of disease are badly needed.  We have developed an experimental model system that uses slices made from rat and mouse brains to create a test platform to research new treatments for brain diseases such as stroke, Alzheimer's disease, Huntington's disease and brain tumors. This model system reduces the number of experimental animals used, and streamlines experiments so that final testing in laboratory animals is more efficient. We use this brainslice system and limited numbers of experimental animals to test drugs and genetic pathways to treat stroke, Alzheimer's disease, Huntington's disease and brain tumors. As many brain tumors are treated with radiation therapy, we have a particular interest in the cellular response to DNA damage caused by radiation. DNA damage signaling and repair are fundamental processes necessary for cells to maintain genomic integrity. Problems with these processes can lead to cancer. As many cancer cells have altered DNA damage and repair pathways, we can apply DNA damage as cancer therapy. Our knowledge of how normal and neoplastic cells handle DNA damage is still incomplete. A deeper understanding can lead to improved cancer treatment, and to better protection from the harmful effects of DNA damaging agents like radiation. To this end, we plan experiments that test the effects of radiation on normal animal tissues and animal models of cancer, as well as molecular pathways in brain diseases such as Alzheimer’s, Huntington’s and stroke.

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