Winter Georg E, Mayer Andreas, Buckley Dennis L, Erb Michael A, Roderick Justine E, Vittori Sarah, Reyes Jaime M, di Iulio Julia, Souza Amanda, Ott Christopher J, Roberts Justin M, Zeid Rhamy, Scott Thomas G, Paulk Joshiawa, Lachance Kate, Olson Calla M, Dastjerdi Shiva, Bauer Sophie, Lin Charles Y, Gray Nathanael S, Kelliher Michelle A, Churchman L Stirling, Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29.
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.
RNA聚合酶II从近端启动子暂停状态进行的持续延伸是人类基因调控中的一个限速事件。少数调节因子在全球范围内影响转录延伸。先前使用小分子BET溴结构域抑制剂（如JQ1）的研究将BRD4与有限数量的与大量增强子区域相关基因的上下文特异性延伸联系起来。在这里，对BET溴结构域蛋白的优化化学降解剂dBET6的机制表征，意外地将BET蛋白鉴定为全球转录延伸的主要调节因子。与溴结构域抑制对转录的选择性作用相反，BET降解会促使全球延伸的崩溃，这与CDK9抑制的表型相似。值得注意的是，BRD4的缺失并不直接影响CDK9的定位。这些在T细胞白血病翻译模型中进行的研究，为开发BET溴结构域降解作为癌症治疗方法建立了基于机制的理论依据。
