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Mol Cell. 2019 Feb 7;73(3):621-638.e17. doi: 10.1016/j.molcel.2018.11.006. Epub 2018 Dec 13.

Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.

Author information

1
Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
2
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
3
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
4
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada.
5
Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada; Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
6
Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland.
7
Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
8
Center for Computational Mass Spectrometry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
9
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, Canada; Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada.
10
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: panagis.filippakopoulos@sgc.ox.ac.uk.
11
Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: gingras@lunenfeld.ca.

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.

KEYWORDS:

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

PMID:
30554943
PMCID:
PMC6375729
DOI:
10.1016/j.molcel.2018.11.006
[Indexed for MEDLINE]
Free PMC Article

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