2. Academic Validation
  3. 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

  • Mol Cell. 2017 Jul 6;67(1):5-18.e19. doi: 10.1016/j.molcel.2017.06.004.
Georg E Winter 1,  Andreas Mayer 2,  Dennis L Buckley 3,  Michael A Erb 3,  Justine E Roderick 4,  Sarah Vittori 3,  Jaime M Reyes 3,  Julia di Iulio 2,  Amanda Souza 3,  Christopher J Ott 3,  Justin M Roberts 3,  Rhamy Zeid 3,  Thomas G Scott 3,  Joshiawa Paulk 3,  Kate Lachance 2,  Calla M Olson 5,  Shiva Dastjerdi 3,  Sophie Bauer 6,  Charles Y Lin 3,  Nathanael S Gray 5,  Michelle A Kelliher 4,  L Stirling Churchman 7,  James E Bradner 8
Affiliations

Affiliations

  • 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: [email protected].
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 28673542 DOI: 10.1016/j.molcel.2017.06.004
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.

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