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Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes

View ORCID ProfileLaura M. Doherty, View ORCID ProfileCaitlin E. Mills, View ORCID ProfileSarah A. Boswell, Xiaoxi Liu, View ORCID ProfileCharles Tapley Hoyt, View ORCID ProfileBenjamin M. Gyori, View ORCID ProfileSara J. Buhrlage, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2021.08.06.455458
Laura M. Doherty
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
2Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Caitlin E. Mills
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Sarah A. Boswell
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Xiaoxi Liu
2Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
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Charles Tapley Hoyt
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Benjamin M. Gyori
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Sara J. Buhrlage
2Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • For correspondence: saraj_buhrlage@dfci.harvard.edu peter_sorger@hms.harvard.edu sorger_admin@hms.harvard.edu
Peter K. Sorger
1Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center, Boston, Massachusetts 02115, USA
4Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • For correspondence: saraj_buhrlage@dfci.harvard.edu peter_sorger@hms.harvard.edu sorger_admin@hms.harvard.edu
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ABSTRACT

Deubiquitinating enzymes (DUBs) are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. Inhibition of DUBs promises to make classically undruggable targets such as the tumor suppressor TP53 and oncogene c-Myc amenable to regulation by small molecules. 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 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, which are browsable online via the DUB Portal, promise to improve understanding of DUBs as a family as well as the activities of specific DUBs such as USP14, UCHL5 and USP7, which have been targeted with investigational cancer therapeutics.

Competing Interest Statement

PKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software; PKS is also a member of the NanoString and Montain Health SABs. In the last five years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships have influenced the content of this manuscript. SJB is a member of the SAB of Adenoid Cystic Carcinoma Foundation. In the last five years the Buhrlage lab has received research funding from AbbVie and in-kind resources from Novartis Institutes for Biomedical Research. Buhrlage declares that none of these relationships have influenced the content of this manuscript. SAB is currently an employee of Ginkgo Bioworks, she declares no conflicts of interest. The other authors declare no outside interests.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 09, 2021.
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Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes
Laura M. Doherty, Caitlin E. Mills, Sarah A. Boswell, Xiaoxi Liu, Charles Tapley Hoyt, Benjamin M. Gyori, Sara J. Buhrlage, Peter K. Sorger
bioRxiv 2021.08.06.455458; doi: https://doi.org/10.1101/2021.08.06.455458
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Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes
Laura M. Doherty, Caitlin E. Mills, Sarah A. Boswell, Xiaoxi Liu, Charles Tapley Hoyt, Benjamin M. Gyori, Sara J. Buhrlage, Peter K. Sorger
bioRxiv 2021.08.06.455458; doi: https://doi.org/10.1101/2021.08.06.455458

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