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      The structure and function of deubiquitinases: lessons from budding yeast

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          Abstract

          Protein ubiquitination is a key post-translational modification that regulates diverse cellular processes in eukaryotic cells. The specificity of ubiquitin (Ub) signalling for different bioprocesses and pathways is dictated by the large variety of mono-ubiquitination and polyubiquitination events, including many possible chain architectures. Deubiquitinases (DUBs) reverse or edit Ub signals with high sophistication and specificity, forming an integral arm of the Ub signalling machinery, thus impinging on fundamental cellular processes including DNA damage repair, gene expression, protein quality control and organellar integrity. In this review, we discuss the many layers of DUB function and regulation, with a focus on insights gained from budding yeast. Our review provides a framework to understand key aspects of DUB biology.

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          Most cited references169

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          Regulation of chromatin by histone modifications.

          Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.
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            A genomic and functional inventory of deubiquitinating enzymes.

            Posttranslational modification of proteins by the small molecule ubiquitin is a key regulatory event, and the enzymes catalyzing these modifications have been the focus of many studies. Deubiquitinating enzymes, which mediate the removal and processing of ubiquitin, may be functionally as important but are less well understood. Here, we present an inventory of the deubiquitinating enzymes encoded in the human genome. In addition, we review the literature concerning these enzymes, with particular emphasis on their function, specificity, and the regulation of their activity.
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              Recognition and processing of ubiquitin-protein conjugates by the proteasome.

              The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                October 2020
                21 October 2020
                21 October 2020
                : 10
                : 10
                : 200279
                Affiliations
                [1 ]Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Toronto, Ontario, Canada M5S 3E1
                [2 ]Department of Molecular Genetics, University of Toronto , Toronto, Ontario, Canada M5S 3E1
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-8286-8991
                http://orcid.org/0000-0001-6427-6493
                Article
                rsob200279
                10.1098/rsob.200279
                7653365
                33081638
                3e24553a-35df-4689-bf1c-9ea4ff6e41b9
                © 2020 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 31 August 2020
                : 23 September 2020
                Funding
                Funded by: Canadian Institutes of Health Research, http://dx.doi.org/10.13039/501100000024;
                Award ID: FDN-143265
                Categories
                33
                15
                129
                Review
                Review Article
                Custom metadata
                October 2020

                Life sciences
                deubiquitinases,protein degradation,ubiquitin signalling
                Life sciences
                deubiquitinases, protein degradation, ubiquitin signalling

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