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  BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment

Winter, G. E., Mayer, A., Buckley, D. L., Erb, M. A., Roderick, J. E., Vittori, S., et al. (2017). BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Molecular Cell, 67(1), 5-18. doi:10.1016/j.molcel.2017.06.004.

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Winter.pdf (Publisher version), 7MB
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 Creators:
Winter, Georg E. , Author
Mayer, Andreas1, 2, Author              
Buckley, Dennis L. , Author
Erb, Michael A. , Author
Roderick, Justine E. , Author
Vittori, Sarah , Author
Reyes,, Jaime M. , Author
di Iulio, Julia , Author
Souza, Amanda , Author
Ott, Christopher J. , Author
Roberts, Justin M. , Author
Zeid, Rhamy , Author
Scott, Thomas G. , Author
Paulk, Joshiawa , Author
Lachance, Kate , Author
Olson, Calla M. , Author
Dastjerdi, Shiva , Author
Bauer, Sophie, Author
Lin, Charles Y. , Author
Gray, Nathanael S. , Author
Kelliher, Michelle A. , AuthorChurchman, L. Stirling , AuthorBradner, James E. , Author more..
Affiliations:
1Nascent Transcription and Cell Differentiation (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385699              
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA, ou_persistent22              

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Free keywords: BRD4; CRBN; P-TEFb; RNA polymerase II; T-ALL; core regulatory circuitry; targeted degradation; transcription elongation
 Abstract: Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.

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Language(s): eng - English
 Dates: 2017-06-022017-06-292017-07-06
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.molcel.2017.06.004
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Title: Molecular Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 67 (1) Sequence Number: - Start / End Page: 5 - 18 Identifier: ISSN: 1097-2765
CoNE: https://pure.mpg.de/cone/journals/resource/954925610929