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dc.contributor.authorWinter, Georg E.
dc.contributor.authorRoderick, Justine E.
dc.contributor.authorKelliher, Michelle A.
dc.contributor.authorBradner, James E.
dc.date2022-08-11T08:09:19.000
dc.date.accessioned2022-08-23T16:26:40Z
dc.date.available2022-08-23T16:26:40Z
dc.date.issued2017-07-06
dc.date.submitted2017-08-29
dc.identifier.citationMol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29. <a href="https://doi.org/10.1016/j.molcel.2017.06.004">Link to article on publisher's site</a>
dc.identifier.issn1097-2765 (Linking)
dc.identifier.doi10.1016/j.molcel.2017.06.004
dc.identifier.pmid28673542
dc.identifier.urihttp://hdl.handle.net/20.500.14038/36612
dc.description<p>Full list of authors omitted for brevity. For full list see article.</p>
dc.description.abstractProcessive 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28673542&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1016/j.molcel.2017.06.004
dc.subjectBiochemistry
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectMolecular Biology
dc.titleBET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment
dc.typeJournal Article
dc.source.journaltitleMolecular cell
dc.source.volume67
dc.source.issue1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/metnet_pubs/130
dc.identifier.contextkey10678124
html.description.abstract<p>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.</p>
dc.identifier.submissionpathmetnet_pubs/130
dc.contributor.departmentUMass Metabolic Network
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.source.pages5-18.e19


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