Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

Mol Cell. 2019 Feb 7;73(3):621-638.e17. doi: 10.1016/j.molcel.2018.11.006. Epub 2018 Dec 13.

Abstract

Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.

Keywords: AP-MS; BET; JQ1; KacY; bromodomain; nucleolus; protein crystallography; proteomic network; rRNA; rewiring.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • K562 Cells
  • Models, Molecular
  • Molecular Targeted Therapy / methods*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Interaction Maps / drug effects*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteomics / methods
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • BRDT protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • Triazoles
  • Protein-Serine-Threonine Kinases