Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

• Published in: Molecular cell Vol. 73; no. 3; pp. 621 - 638.e17
• Main Authors: Lambert, Jean-Philippe, Picaud, Sarah, Fujisawa, Takao, Hou, Huayun, Savitsky, Pavel, Uusküla-Reimand, Liis, Gupta, Gagan D., Abdouni, Hala, Lin, Zhen-Yuan, Tucholska, Monika, Knight, James D.R., Gonzalez-Badillo, Beatriz, St-Denis, Nicole, Newman, Joseph A., Stucki, Manuel, Pelletier, Laurence, Bandeira, Nuno, Wilson, Michael D., Filippakopoulos, Panagis, Gingras, Anne-Claude
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-02-2019; Cell Press
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; AP-MS; Azepines - chemistry; Azepines - pharmacology; BET; bromodomain; Cell Cycle Proteins; Cell Proliferation - drug effects; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Humans; JQ1; K562 Cells; KacY; 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; nucleolus; Protein Binding; Protein Conformation; protein crystallography; 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; proteomic network; Proteomics - methods; rewiring; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; rRNA; Signal Transduction - drug effects; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Triazoles - chemistry; Triazoles - pharmacology; BET; bromodomain; protein crystallography; rRNA; nucleolus; proteomic network; JQ1; rewiring; AP-MS; KacY
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.11.006

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.
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•Treatment with JQ1 induces an extensive BET proteins interactome rewiring•Structural and biophysical studies expand the target space for BET bromodomains•Two distinct short linear motifs mediate BET ET domain interactions•BRD3 negatively regulates proliferation through Pol I and II mechanisms
Lambert, Picaud, et al. report that pharmacological bromodomain inhibition rewires the interactome of the Bromo and Extra-Terminal (BET) proteins, resulting in loss (e.g., histones), maintenance, or gain of interactions. They reveal new binding modalities and an unsuspected negative role for BRD3 in proliferation.