2017
DOI: 10.1016/j.molcel.2017.06.004
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BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment

Abstract: SUMMARY 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 prot… Show more

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Cited by 378 publications
(452 citation statements)
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“…We further utilize a series of compounds, which were synthesized to bind CRBN and the bromodomains of BRD4 (see Supplementary Fig. 1b) 6,10 . These molecules comprise the E3-moiety thalidomide to bind to CRL4 CRBN , a flexible linker of variable length and composition, and a target-moiety, JQ1, that binds to BRD4 BD1 and BRD4 BD2 with equal affinities 29 .…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…We further utilize a series of compounds, which were synthesized to bind CRBN and the bromodomains of BRD4 (see Supplementary Fig. 1b) 6,10 . These molecules comprise the E3-moiety thalidomide to bind to CRL4 CRBN , a flexible linker of variable length and composition, and a target-moiety, JQ1, that binds to BRD4 BD1 and BRD4 BD2 with equal affinities 29 .…”
Section: Resultsmentioning
confidence: 99%
“…Significant progress has recently been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands (often referred to as degraders or PROTACs for PROteolysis-TArgeting Chimeras) 110 . Targeted protein degradation refers to small molecule induced ubiquitination and degradation of disease targets, in which a small molecule simultaneously recruits both a ubiquitin E3 ligase and the target protein to be ubiquitinated (Supplementry Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Next, we sought to determine whether THAL-SNS-032 could induce degradation of the primary CDK targets of SNS-032 by treating wildtype and CRBN −/− MOLT4 cells 28 with increasing concentrations of THAL-SNS-032 for 6 hours. We found that while CDK9 degradation is CRBN-dependent up to a concentration of 5μM, the other known CDK targets of SNS-032 show little-to-no change in protein levels at any of the tested concentrations (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Genes, characterized by BRD4-binding solely to promoters/TSS, will not be affected by BET inhibition and are expected to require combination with CDK9 inhibition to stall transcriptional elongation. Notably, the effects observed via targeted BRD4 protein degradation, either by PROTACs or by an inducible system are mechanistically similar to the consequences of combined BET/CDK9-inhibition [3, 5]. We find it striking that BRD4-degradation has such a drastic effect on transcriptional elongation without affecting CDK9 recruitment [5].…”
mentioning
confidence: 86%
“…Notably, the effects observed via targeted BRD4 protein degradation, either by PROTACs or by an inducible system are mechanistically similar to the consequences of combined BET/CDK9-inhibition [3, 5]. We find it striking that BRD4-degradation has such a drastic effect on transcriptional elongation without affecting CDK9 recruitment [5]. Hence one can speculate that CDK9 may globally regulate BRD4's proposed function as an elongation factor and histone chaperone [4].…”
mentioning
confidence: 95%