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Journal of Neurochemistry Apr 2021Circadian clocks are internal timing systems that enable organisms to adjust their behavioral and physiological rhythms to the daily changes of their environment. These... (Review)
Review
Circadian clocks are internal timing systems that enable organisms to adjust their behavioral and physiological rhythms to the daily changes of their environment. These clocks generate self-sustained oscillations at the cellular, tissue, and behavioral level. The rhythm-generating mechanism is based on a gene expression network with a delayed negative feedback loop that causes the transcripts to oscillate with a period of approximately 24 hr. This oscillatory nature of the proteins involved in this network necessitates that they are intrinsically unstable, with a short half-life. Hence, post-translational modifications (PTMs) are important to precisely time the presence, absence, and interactions of these proteins at appropriate times of the day. Ubiquitination and deubiquitination are counter-balancing PTMs which play a key role in this regulatory process. In this review, we take a comprehensive look at the roles played by the processes of ubiquitination and deubiquitination in the clock machinery of the most commonly studied eukaryotic models of the circadian clock: plants, fungi, fruit flies, and mammals. We present the effects exerted by ubiquitinating and deubiquitinating enzymes on the stability, but also the activity, localization, and interactions of clock proteins. Overall, these PTMs have key roles in regulating not only the pace of the circadian clocks but also their response to external cues and their control of cellular functions.
Topics: Animals; CLOCK Proteins; Circadian Clocks; Circadian Rhythm; Drosophila; Humans; Protein Processing, Post-Translational; Ubiquitination
PubMed: 32717140
DOI: 10.1111/jnc.15132 -
DNA Repair Aug 2016Nucleotide excision repair (NER) protects genome stability by eliminating DNA helix distorting lesions, such as those induced by UV radiation. The addition and removal... (Review)
Review
Nucleotide excision repair (NER) protects genome stability by eliminating DNA helix distorting lesions, such as those induced by UV radiation. The addition and removal of ubiquitin, namely, ubiquitination and deubiquitination, have recently been demonstrated as general mechanisms to regulate protein functions. Accumulating evidence shows that several NER factors are subjected to extensive regulation by ubiquitination and deubiquitination. Thus, the balance between E3 ligases and deubiquitinating enzyme activities can dynamically alter the ubiquitin landscape at DNA damage sites, thereby regulating NER efficiency. Current knowledge about XPC ubiquitination by different ubiquitin E3 ligases highlights the importance of ubiquitin linkage types in regulating XPC binding and release from damaged DNA. Here, we discuss the emerging roles of deubiquitinating enzymes and their ubiquitin linkage specificities in NER.
Topics: Chromatin; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Genome, Human; Humans; Isoenzymes; Nuclear Proteins; Protein Binding; Protein Processing, Post-Translational; Ubiquitin; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases; Ubiquitination; Ultraviolet Rays
PubMed: 27316462
DOI: 10.1016/j.dnarep.2016.05.035 -
Methods in Molecular Biology (Clifton,... 2023Deubiquitinating enzymes cleave ubiquitin (Ub) from its attachment to another Ub, other proteins, peptides, or non-peptide adducts. In all cases, substrate hydrolysis by...
Deubiquitinating enzymes cleave ubiquitin (Ub) from its attachment to another Ub, other proteins, peptides, or non-peptide adducts. In all cases, substrate hydrolysis by DUBs releases free Ub or polyubiquitin (polyUb) chains. Whereas most quantitative DUB assays depend on fluorescently labeled artificial substrates, employing a sensor able to detect Ub release in real time makes it possible to monitor DUB activity using virtually any Ub conjugate as a substrate. The protocols here describe the preparation of Atto532-tUI, a high-affinity sensor for free Ub, and its use in real-time deubiquitination assays.
Topics: Ubiquitin; Ubiquitination; Polyubiquitin; Hydrolysis
PubMed: 36350553
DOI: 10.1007/978-1-0716-2803-4_15 -
F1000Research 2016A majority of proteins in the cell can be modified by ubiquitination, thereby altering their function or stability. This ubiquitination is controlled by both... (Review)
Review
A majority of proteins in the cell can be modified by ubiquitination, thereby altering their function or stability. This ubiquitination is controlled by both ubiquitinating and deubiquitinating enzymes (DUBs). The number of ubiquitin ligases exceeds that of DUBs by about eightfold, indicating that DUBs may have much broader substrate specificity. Despite this, DUBs have been shown to have quite specific physiological functions. This functional specificity is likely due to very precise regulation of activity arising from the sophisticated use of all mechanisms of enzyme regulation. In this commentary, we briefly review key features of DUBs with more emphasis on regulation. In particular, we focus on localization of the enzymes as a critical regulatory mechanism which when integrated with control of expression, substrate activation, allosteric regulation, and post-translational modifications results in precise spatial and temporal deubiquitination of proteins and therefore specific physiological functions. Identification of compounds that target the structural elements in DUBs that dictate localization may be a more promising approach to development of drugs with specificity of action than targeting the enzymatic activity, which for most DUBs is dependent on a thiol group that can react non-specifically with many compounds in large-scale screening.
PubMed: 26918171
DOI: 10.12688/f1000research.7220.1 -
Stem Cells International 2016Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a... (Review)
Review
Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a timely and well-coordinated manner to regulate the protein turnover of several stemness related proteins, resulting in optimal embryonic stem cell maintenance and differentiation. There are two switches: an E3 ubiquitin ligase enzyme that tags ubiquitin molecules to the target proteins for proteolysis and a second enzyme, the deubiquitinating enzyme (DUBs), that performs the opposite action, thereby preventing proteolysis. In order to maintain stemness and to allow for efficient differentiation, both ubiquitination and deubiquitination molecular switches must operate properly in a balanced manner. In this review, we have summarized the importance of the ubiquitination of core stem cell transcription factors, such as Oct3/4, c-Myc, Sox2, Klf4, Nanog, and LIN28, during cellular reprogramming. Furthermore, we emphasize the role of DUBs in regulating core stem cell transcriptional factors and their function in stem cell maintenance and differentiation. We also discuss the possibility of using DUBs, along with core transcription factors, to efficiently generate induced pluripotent stem cells. Our review provides a relatively new understanding regarding the importance of ubiquitination/deubiquitination of stem cell transcription factors for efficient cellular reprogramming.
PubMed: 26880980
DOI: 10.1155/2016/6705927 -
Translational Oncology Aug 2023The elevated Cyclin B1 expression contributes to various tumorigenesis and poor prognosis. Cyclin B1 expression could be regulated by ubiquitination and...
BACKGROUND
The elevated Cyclin B1 expression contributes to various tumorigenesis and poor prognosis. Cyclin B1 expression could be regulated by ubiquitination and deubiquitination. However, the mechanism of how Cyclin B1 is deubiquitinated and its roles in human glioma remain unclear.
METHODS
Co-immunoprecipitation and other assays were performed to detect the interacting of Cyclin B1 and USP39. A series of in vitro and in vivo experiments were performed to investigate the effect of USP39 on the tumorigenicity of tumor cells.
RESULTS
USP39 interacts with Cyclin B1 and stabilizes its expression by deubiquitinating Cyclin B1. Notably, USP39 cleaves the K29-linked polyubiquitin chain on Cyclin B1 at Lys242. Additionally, overexpression of Cyclin B1 rescues the arrested cell cycle at G2/M transition and the suppressed proliferation of glioma cells caused by USP39 knockdown in vitro. Furthermore, USP39 promotes the growth of glioma xenograft in subcutaneous and in situ of nude mice. Finally, in human tumor specimens, the expression levels of USP39 and Cyclin B1 are positively relevant.
CONCLUSION
Our data support the evidence that USP39 acts a novel deubiquitinating enzyme of Cyclin B1 and promoted tumor cell proliferation at least in part through Cyclin B1 stabilization, represents a promising therapeutic strategy for tumor patients.
PubMed: 37302347
DOI: 10.1016/j.tranon.2023.101713 -
Biochimica Et Biophysica Acta. Reviews... May 2022The mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation,... (Review)
Review
The mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation, and stress responses. This pathway converts external stimuli to cellular responses via three major kinases: mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase (MAPKK), and mitogen-activated protein kinase kinase kinase (MAPKKK). Ubiquitination is a post-translational modification of proteins with ubiquitin, which results in the formation of mono- or poly-ubiquitin chains of substrate proteins. Conversely, removal of the ubiquitin by deubiquitinating enzymes (DUBs) is known as deubiquitination. This review summarizes mechanisms of the MAPK signaling pathways (ERK1/2, ERK5, p38, and JNK1/2/3 signaling pathway) in cancers, and of E3 ligases and DUBs that target the MAPK signaling components such as Raf, MEK1/2, ERK1/2, MEKK2/3, MEKK1-4, TAK1, DLK1, MLK1-4, ASK1/2, and MKK3-7.
Topics: Deubiquitinating Enzymes; Enzyme Activation; Humans; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Signal Transduction; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 35589008
DOI: 10.1016/j.bbcan.2022.188736 -
Future Oncology (London, England) Feb 2011The post-translational modification of different proteins via direct ubiquitin attachment is important for various cellular processes. Dysregulation of components of the... (Review)
Review
The post-translational modification of different proteins via direct ubiquitin attachment is important for various cellular processes. Dysregulation of components of the ubiqutin system have been linked to many diseases including cancer. CYLD is a deubiquitination enzyme that can cleave the lysine 63-linked polyubiquitin chains from target proteins and regulate cell survival or cell proliferation. Since loss of CYLD expression can be observed in different types of human cancer, it is now well established that CYLD acts as a tumor suppressor gene. Besides its loss of function in human tumors by gene deletion or mutation, CYLD expression can be downregulated at the RNA level if necessary through transcriptional regulation or at the protein level through post-translational modifications. This article summarizes recent advances that link CYLD to different types of human cancer. Identification of CYLD-mediated signaling pathways during the progression of cancer will provide a solid foundation for diagnosis and lead to the development of novel tools for cancer therapy.
Topics: Animals; Deubiquitinating Enzyme CYLD; Humans; NF-kappa B; Neoplasms; Protein Processing, Post-Translational; Signal Transduction; Tumor Suppressor Proteins; Ubiquitination
PubMed: 21345146
DOI: 10.2217/fon.10.187 -
Biochemical Society Transactions Feb 2010Deubiquitination is a crucial mechanism in ubiquitin-mediated signalling networks. The importance of Dubs (deubiquitinating enzymes) as regulators of diverse cellular... (Review)
Review
Deubiquitination is a crucial mechanism in ubiquitin-mediated signalling networks. The importance of Dubs (deubiquitinating enzymes) as regulators of diverse cellular processes is becoming ever clearer as new roles are elucidated and new pathways are shown to be affected by this mechanism. Recent work, reviewed in the present paper, provides new perspective on the widening influence of Dubs and a new tool to focus studies of not only Dub interactions, but also potentially many more cellular systems.
Topics: Endopeptidases; Humans; Reproducibility of Results; Signal Transduction; Ubiquitin; Ubiquitin Thiolesterase
PubMed: 20074029
DOI: 10.1042/BST0380021 -
The Journal of Biological Chemistry Sep 2021Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity,... (Review)
Review
Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein-protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.
Topics: Animals; Deubiquitinating Enzymes; Endopeptidases; Homeostasis; Humans; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Reactive Oxygen Species; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 34391779
DOI: 10.1016/j.jbc.2021.101077