BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.
BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.
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DOI：
10.1016/j.molcel.2017.06.004
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发表时间：
2017-07-06
期刊：
影响因子：
16
通讯作者：
Bradner JE
中科院分区：
文献类型：
--
作者：
Winter GE;Mayer A;Buckley DL;Erb MA;Roderick JE;Vittori S;Reyes JM;di Iulio J;Souza A;Ott CJ;Roberts JM;Zeid R;Scott TG;Paulk J;Lachance K;Olson CM;Dastjerdi S;Bauer S;Lin CY;Gray NS;Kelliher MA;Churchman LS;Bradner JE
在人类基因控制中，RNA聚合酶II从近端启动子暂停状态的过程延伸是一个限速事件。少数调控因子在全球范围内影响转录延伸。之前使用小分子BET溴域抑制剂，如JQ1的研究，将BRD4与与大量增强子区域相关的有限数量的基因的上下文特定延长联系在一起。在这里，一种优化的BET溴域蛋白的化学降解物dBET6的机制表征导致了BET蛋白意外地被确定为全球转录延伸的主要调节因子。与溴域抑制对转录的选择性作用不同，BET的降解促使表现为CDK9抑制的整体伸长的崩溃。值得注意的是，BRD4缺失并不直接影响CDK9的本地化。这些研究在T细胞白血病的翻译模型中进行，为BET溴域降解作为癌症治疗的发展建立了基于机制的理论基础。温特等人。描述BET溴域抑制和BET蛋白质降解的分子药理学上的根本区别。通过比较研究，我们发现BET蛋白是转录延长的主要调节因子。BET蛋白的急剧降解促使与CDK9募集无关的生产性伸长的全球崩溃。
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. Winter et al. delineate fundamental differences in the molecular pharmacology of BET bromodomain inhibition and BET protein degradation. Comparative studies led to the identification of BET proteins as master regulators of transcription elongation. Acute BET protein degradation prompts a global collapse of productive elongation that is independent of CDK9 recruitment.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM
DOI：
10.1073/pnas.1013828108
发表时间：
2011-01-11
影响因子：
11.1
作者：
Klein, Brianna J.;Bose, Daniel;Murakami, Katsuhiko S.
通讯作者：
Murakami, Katsuhiko S.