期刊
MOLECULAR CELL
卷 73, 期 3, 页码 621-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.11.006
关键词
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资金
- Canadian Institutes of Health Research Foundation [CIHR FDN 143301]
- Genome Canada and Ontario Genomics [OGI-139]
- Natural Sciences and Engineering Research Council of Canada
- US NIH [5P41GM103484]
- Ludwig Institute
- Medical Research Council [MR/N010051/1]
- Wellcome Trust [095751/Z/11/Z, 092809/Z/10/Z]
- TD Bank fellowships
- Cancer Research Society
- Isaiah 40: 31 Memorial Fund
- Uehara Memorial Foundation [201330102]
- Estonian Research Council [PUTJD145]
- University of Toronto
- Sloan Foundation
- Structural Genomics Consortium, a registered charity from AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Early Researcher Award from Ontario
- MRC [MR/N010051/1] Funding Source: UKRI
Targeting bromodomains (BRDs) of the bromo-andextra-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 bindingmotifs 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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