Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

Jean-Philippe Lambert; Sarah Picaud; Takao Fujisawa; Huayun Hou; Pavel Savitsky; Liis Uusküla-Reimand; Gagan D Gupta; Hala Abdouni; Zhen-Yuan Lin; Monika Tucholska; James D R Knight; Beatriz Gonzalez-Badillo; Nicole St-Denis; Joseph A Newman; Manuel Stucki; Laurence Pelletier; Nuno Bandeira; Michael D Wilson; Panagis Filippakopoulos; Anne-Claude Gingras

doi:10.1016/j.molcel.2018.11.006

Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains

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

Authors

Jean-Philippe Lambert¹, Sarah Picaud², Takao Fujisawa³, Huayun Hou⁴, Pavel Savitsky², Liis Uusküla-Reimand⁵, Gagan D Gupta¹, Hala Abdouni¹, Zhen-Yuan Lin¹, Monika Tucholska¹, James D R Knight¹, Beatriz Gonzalez-Badillo¹, Nicole St-Denis¹, Joseph A Newman², Manuel Stucki⁶, Laurence Pelletier⁷, Nuno Bandeira⁸, Michael D Wilson⁹, Panagis Filippakopoulos¹⁰, Anne-Claude Gingras¹¹

Affiliations

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Azepines / chemistry
Azepines / pharmacology*
Cell Cycle Proteins
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Humans
K562 Cells
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
Protein Binding
Protein Conformation
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
Proteomics / methods
RNA-Binding Proteins / antagonists & inhibitors*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Signal Transduction / drug effects
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / genetics
Transcription Factors / metabolism
Triazoles / chemistry
Triazoles / pharmacology*

Substances

(+)-JQ1 compound
Antineoplastic Agents
Azepines
BRD2 protein, human
BRD3 protein, human
BRD4 protein, human
BRDT protein, human
Cell Cycle Proteins
Nuclear Proteins
RNA-Binding Proteins
Transcription Factors
Triazoles
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding