Regulation and Cellular Roles of Ubiquitin-specific Deubiquitinating Enzymes

• Authors: Francisca E. Reyes-Turcu, Emory University; Karen H. Ventii, Emory University; Keith D Wilkinson, Emory University
• Journal Title: Annual Review of Biochemistry
• Volume: Volume 78
• Publisher: Annual Reviews | 2009, Pages 363-397
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1146/annurev.biochem.78.082307.091526
• Subjects: Chemistry, Biochemistry; Health Sciences, General; Biology, Cell
• Keywords: Ubiquitin; Proteasome; Histone; Cell cycle; Endocytosis; DNA Damage; Signal Transduction

Abstract

Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin (or ubiquitin-like protein), and remodel polyubiquitin (or ubiquitin-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five families: the UCH, USP, OTU, Josephin, and JAMM families. Four families are cysteine proteases, while the later is a family of metalloproteases. Most DUB activity is cryptic and active site rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain multiple domains with insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multi-protein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have lead to new insights into the function of yeast and human DUBs. This review will discuss ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes. Specific examples are drawn from studies of protein degradation, DNA repair, chromatin remodeling, cell cycle regulation, endocytosis, and modulation of signaling kinases.