Interactome rewiring following pharmacological targeting of BET bromodomains

DOI: 10.1016/j.molcel.2018.11.006

Authors: Jean-Philippe Lambert (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Takao Fujisawa (Ludwig Institute for Cancer Research, University of Oxford) , Huayun Hou (University of Toronto; SickKids Research Institute) , Pavel Savitsky (Structural Genomics Consortium, University of Oxford) , Liis Uusküla-Reimand (SickKids Research Institute; Tallinn University of Technology) , Gagan D. Gupta (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital; Ryerson University) , Hala Abdouni (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Zhen-Yuan Lin (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Monika Tucholska (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , James D. R. Knight (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Beatriz Gonzalez-Badillo (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Nicole St-Denis (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital) , Joseph A. Newman (Structural Genomics Consortium, University of Oxford) , Manuel Stucki (University of Zurich) , Laurence Pelletier (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital; University of Toronto) , Nuno Bandeira (University of California, San Diego) , Michael D. Wilson (University of Toronto; SickKids Research Institute; Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research) , Panagis Filippakopoulos (Ludwig Institute for Cancer Research; Structural Genomics Consortium, University of Oxford;) , Anne-Claude Gingras (Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital; University of Toronto)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 6391 , 10619 , 15433

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.

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

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS , I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 18/12/2018 15:21

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)