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Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004. Epub 2017 Jun 29.

BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.

Author information

1
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.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
7
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: churchman@genetics.med.harvard.edu.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: james.bradner@novartis.com.

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.

KEYWORDS:

BRD4; CRBN; P-TEFb; RNA polymerase II; T-ALL; core regulatory circuitry; targeted degradation; transcription elongation

PMID:
28673542
PMCID:
PMC5663500
DOI:
10.1016/j.molcel.2017.06.004
[Indexed for MEDLINE]
Free PMC Article

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