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Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

Jean-Philippe Lambert1, Sarah Picaud2, Takao Fujisawa3

  • 1Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.

Molecular Cell
|December 18, 2018
PubMed

Insights

Bromodomain (BRD) inhibitors like JQ1 rewire protein interactions in bromo-and-extra-terminal (BET) proteins. This study reveals new binding modes and negative regulatory roles for BRD3, impacting cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family are therapeutic targets for cancer and other diseases.
  • Understanding BET protein interactions is crucial for developing effective therapies.

Purpose of the Study:

  • To profile the interactomes of BRD2, BRD3, BRD4, and BRDT after treatment with the pan-BET inhibitor JQ1.
  • To characterize the distinct classes of protein interactions mediated by BET proteins and their response to JQ1.

Main Methods:

  • Proteomic analysis of BRD2, BRD3, BRD4, and BRDT interactomes.
  • Treatment with the pan-BET inhibitor JQ1.
  • Identification and classification of protein interactors.

Main Results:

  • 603 unique interactors were identified, showing three distinct classes of behavior upon JQ1 treatment.
  • JQ1-sensitive associations via canonical and novel binding modes were observed.
  • Acetylation-independent interactions mediated by extra-terminal (ET)-domain binding motifs were characterized.
  • Unexpected increases in BRD3 interactions revealed negative regulatory roles in rRNA synthesis and gene expression, decreasing cell proliferation.

Conclusions:

  • BET protein modules significantly contribute to their interactomes.
  • Pharmacological targeting of BET proteins with JQ1 induces broad rewiring of protein interactions.
  • The study provides insights into acetylation-independent interactions and identifies novel negative regulatory functions of BRD3.
Keywords:
AP-MSBETJQ1KacYbromodomainnucleolusprotein crystallographyproteomic networkrRNArewiring

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