Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains
Copyright policy )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.
- University of California System United States
- University of Zurich Switzerland
- University of California, San Diego United States
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD United Kingdom
- University of Oxford United Kingdom
Models, Molecular, Proteomics, Protein Conformation, 610 Medicine & health, Antineoplastic Agents, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Article, 1307 Cell Biology, Neoplasms, 1312 Molecular Biology, Humans, Protein Interaction Domains and Motifs, Molecular Targeted Therapy, Protein Interaction Maps, Cell Proliferation, Nuclear Proteins, RNA-Binding Proteins, Azepines, 10174 Clinic for Gynecology, Gene Expression Regulation, Neoplastic, HEK293 Cells, K562 Cells, HeLa Cells, Protein Binding
Models, Molecular, Proteomics, Protein Conformation, 610 Medicine & health, Antineoplastic Agents, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Article, 1307 Cell Biology, Neoplasms, 1312 Molecular Biology, Humans, Protein Interaction Domains and Motifs, Molecular Targeted Therapy, Protein Interaction Maps, Cell Proliferation, Nuclear Proteins, RNA-Binding Proteins, Azepines, 10174 Clinic for Gynecology, Gene Expression Regulation, Neoplastic, HEK293 Cells, K562 Cells, HeLa Cells, Protein Binding
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