Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.

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.
Mesh Terms:
Antineoplastic Agents, Azepines, Cell Cycle Proteins, Cell Proliferation, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, K562 Cells, Models, Molecular, Molecular Targeted Therapy, Neoplasms, Nuclear Proteins, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein-Serine-Threonine Kinases, Proteomics, RNA-Binding Proteins, Signal Transduction, Structure-Activity Relationship, Transcription Factors, Triazoles
Mol. Cell
Date: Dec. 07, 2018
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