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. Epub 2017 Jun 29.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Leukemic
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Multiprotein Complexes
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Protein Stability
  • Proteolysis
  • RNA Polymerase II / metabolism
  • Time Factors
  • Transcription Elongation, Genetic* / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Ubiquitin-Protein Ligases
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BRD4 protein, human
  • CRBN protein, human
  • Cell Cycle Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II
  • Peptide Hydrolases