Affiliation:
1. Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center
2. Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute
3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
4. Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School
Abstract
Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They are involved in a wide range of cellular activities and are emerging therapeutic targets for cancer and other diseases. Drugs targeting USP1 and USP30 are in clinical development for cancer and kidney disease respectively. However, the majority of substrates and pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific enzymes for research and drug development. To assemble a knowledgebase of DUB activities, co-dependent genes, and substrates, we combined targeted experiments using CRISPR libraries and inhibitors with systematic mining of functional genomic databases. Analysis of the Dependency Map, Connectivity Map, Cancer Cell Line Encyclopedia, and multiple protein-protein interaction databases yielded specific hypotheses about DUB function, a subset of which were confirmed in follow-on experiments. The data in this paper are browsable online in a newly developed DUB Portal and promise to improve understanding of DUBs as a family as well as the activities of incompletely characterized DUBs (e.g. USPL1 and USP32) and those already targeted with investigational cancer therapeutics (e.g. USP14, UCHL5, and USP7).
Funder
National Institutes of Health
Defense Advanced Research Projects Agency
National Science Foundation
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
13 articles.
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