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The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 41708

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Dr. Suresh Ramakrishna

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Department of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
Interests: signal transduction related to ubiquitination and deubiquitination; factors affecting stem cell maintenance and differentiation; post-translational modifications of transcriptional factors during odontogenesis; genome editing on stem cells to generate several disease models using CRISPR/Cas9 system

Special Issue Information

Dear Colleagues,

Ubiquitination Vs Deubiquitination

Ubiquitination is a Post-translational modification in which ubiquitin is conjugated to a protein substrate, thereby regulating the stability and activity of the modified protein. For a ubiquitin molecule to be attached to a target protein, the sequential actions of three different classes of enzymes–E1 (ubiquitin activating enzymes), E2 (ubiquitin conjugating enzymes), and E3 (ubiquitin ligases)–are required. Ubiquitin is a small and highly conserved 76-amino acid protein with a molecular weight of 8.5 kDa. The ubiquitin modification can be covalently attached to protein substrates as either a monomer or as a polymer. The different ubiquitin modifications depend on the type of chain formed during the process. Substrate proteins can be modified with mono-ubiquitin, multiple monoubiquitin (multi-ubiquitination), or a polyubiquitin chain (polyubiquitination). During polyubiquitination, any of the seven lysine (K) residues (K6,K11, K27, K29, K33, K48, and K63) of ubiquitin can be utilized for the formation of ubiquitin−ubiquitin linkages, resulting in a sizeable chain increase with different configurations called polyubiquitin chains

The deubiquitinating enzymes (DUBs) comprise a class of proteases that cleave ubiquitin molecules from ubiquitin-conjugated protein substrates. Specifically, DUBs selectively cleave the isopeptide bond present at the ubiquitin C-terminus. DUBs prevent proteasome dependent and lysosome-dependent protein degradation because they counteract E3 ligase-mediated ubiquitination. Consequently, DUBs indirectly alter the activities and levels of their target proteins.

The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and DUBs, which determine protein stability. The ubiquitination and deubiquitination molecular switches must operate in a balanced manner to control ubiquitin pool, maintain protein homeostasis, and cellular functions. The action of E3 ligases and DUBs are associated with the development and progress of tumorigenesis by modifying key proteins that regulate the cell cycle, gene transcription, DNA repair, and apoptosis. Similarly, ubiquitination and deubiquitination, which regulate protein turnover of several stemness related proteins, must be carefully coordinated to ensure optimal embryonic stem cell maintenance and differentiation.

This Special Issue welcomes both original papers and review articles addressing one or several of the above issues, or of the topics mentioned in the key words listed below.

Dr. Suresh Ramakrishna
Guest Editor

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Keywords

Ubiquitin-proteasome pathway
Protein degradation and protein stabiliy
DUB inhibitors
E3 ligases inhibitors
Pre-clinical research and Clinical trials
Anti-cancer drug
Drug resistance
Cancer pathogenesis
Therapeutics
Signal transduction
Cell cycle regulation
DNA damage, DNA repair and Cell death
Stem cells regulation
Transcriptional factors regulation
Disease association and progression

Published Papers (12 papers)

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Research

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17 pages, 3067 KiB

Open AccessArticle

USP48 Governs Cell Cycle Progression by Regulating the Protein Level of Aurora B

by Ainsley Mike Antao, Kamini Kaushal, Soumyadip Das, Vijai Singh, Bharathi Suresh, Kye-Seong Kim and Suresh Ramakrishna

Int. J. Mol. Sci. 2021, 22(16), 8508; https://doi.org/10.3390/ijms22168508 - 07 Aug 2021

Cited by 8 | Viewed by 2488

Abstract

Deubiquitinating enzymes play key roles in the precise modulation of Aurora B—an essential cell cycle regulator. The expression of Aurora B increases before the onset of mitosis and decreases during mitotic exit; an imbalance in these levels has a severe impact on the fate of the cell cycle. Dysregulation of Aurora B can lead to aberrant chromosomal segregation and accumulation of errors during mitosis, eventually resulting in cytokinesis failure. Thus, it is essential to identify the precise regulatory mechanisms that modulate Aurora B levels during the cell division cycle. Using a deubiquitinase knockout strategy, we identified USP48 as an important candidate that can regulate Aurora B protein levels during the normal cell cycle. Here, we report that USP48 interacts with and stabilizes the Aurora B protein. Furthermore, we showed that the deubiquitinating activity of USP48 helps to maintain the steady-state levels of Aurora B protein by regulating its half-life. Finally, USP48 knockout resulted in delayed progression of cell cycle due to accumulation of mitotic defects and ultimately cytokinesis failure, suggesting the role of USP48 in cell cycle regulation. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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12 pages, 2311 KiB

Open AccessArticle

Ubiquitin-Specific Protease 29 Regulates Cdc25A-Mediated Tumorigenesis

by Arun Pandian Chandrasekaran, Sang Hyeon Woo, Neha Sarodaya, Byung Ho Rhie, Apoorvi Tyagi, Soumyadip Das, Bharathi Suresh, Na Re Ko, Seung Jun Oh, Kye-Seong Kim and Suresh Ramakrishna

Int. J. Mol. Sci. 2021, 22(11), 5766; https://doi.org/10.3390/ijms22115766 - 28 May 2021

Cited by 11 | Viewed by 2512

Abstract

Cell division cycle 25A (Cdc25A) is a dual-specificity phosphatase that is overexpressed in several cancer cells and promotes tumorigenesis. In normal cells, Cdc25A expression is regulated tightly, but the changes in expression patterns in cancer cells that lead to tumorigenesis are unknown. In this study, we showed that ubiquitin-specific protease 29 (USP29) stabilized Cdc25A protein expression in cancer cell lines by protecting it from ubiquitin-mediated proteasomal degradation. The presence of USP29 effectively blocked polyubiquitination of Cdc25A and extended its half-life. CRISPR-Cas9-mediated knockdown of USP29 in HeLa cells resulted in cell cycle arrest at the G0/G1 phase. We also showed that USP29 knockdown hampered Cdc25A-mediated cell proliferation, migration, and invasion of cancer cells in vitro. Moreover, NSG nude mice transplanted with USP29-depleted cells significantly reduced the size of the tumors, whereas the reconstitution of Cdc25A in USP29-depleted cells significantly increased the tumor size. Altogether, our results implied that USP29 promoted cell cycle progression and oncogenic transformation by regulating protein turnover of Cdc25A. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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16 pages, 6470 KiB

Open AccessArticle

Ubiquitin-Specific Protease 3 Deubiquitinates and Stabilizes Oct4 Protein in Human Embryonic Stem Cells

by Byung-Ho Rhie, Ainsley Mike Antao, Janardhan Keshav Karapurkar, Min-Seong Kim, Won-Jun Jo, Suresh Ramakrishna and Kye-Seong Kim

Int. J. Mol. Sci. 2021, 22(11), 5584; https://doi.org/10.3390/ijms22115584 - 25 May 2021

Cited by 8 | Viewed by 3326

Abstract

Oct4 is an important mammalian POU family transcription factor expressed by early human embryonic stem cells (hESCs). The precise level of Oct4 governs the pluripotency and fate determination of hESCs. Several post-translational modifications (PTMs) of Oct4 including phosphorylation, ubiquitination, and SUMOylation have been reported to regulate its critical functions in hESCs. Ubiquitination and deubiquitination of Oct4 should be well balanced to maintain the pluripotency of hESCs. The protein turnover of Oct4 is regulated by several E3 ligases through ubiquitin-mediated degradation. However, reversal of ubiquitination by deubiquitinating enzymes (DUBs) has not been reported for Oct4. In this study, we generated a ubiquitin-specific protease 3 (USP3) gene knockout using the CRISPR/Cas9 system and demonstrated that USP3 acts as a protein stabilizer of Oct4 by deubiquitinating Oct4. USP3 interacts with endogenous Oct4 and co-localizes in the nucleus of hESCs. The depletion of USP3 leads to a decrease in Oct4 protein level and loss of pluripotent morphology in hESCs. Thus, our results show that USP3 plays an important role in controlling optimum protein level of Oct4 to retain pluripotency of hESCs. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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19 pages, 4297 KiB

Open AccessArticle

The Grapevine E3 Ubiquitin Ligase VriATL156 Confers Resistance against the Downy Mildew Pathogen Plasmopara viticola

by Elodie Vandelle, Pietro Ariani, Alice Regaiolo, Davide Danzi, Arianna Lovato, Claudia Zadra, Nicola Vitulo, Giorgio Gambino and Annalisa Polverari

Int. J. Mol. Sci. 2021, 22(2), 940; https://doi.org/10.3390/ijms22020940 - 19 Jan 2021

Cited by 4 | Viewed by 2620

Abstract

Downy mildew, caused by Plasmopara viticola, is one of the most severe diseases of grapevine (Vitis vinifera L.). Genetic resistance is an effective and sustainable control strategy, but major resistance genes (encoding receptors for specific pathogen effectors) introgressed from wild Vitis species, although effective, may be non-durable because the pathogen can evolve to avoid specific recognition. Previous transcriptomic studies in the resistant species Vitis riparia highlighted the activation of signal transduction components during infection. The transfer of such components to V. vinifera might confer less specific and therefore more durable resistance. Here, we describe the generation of transgenic V. vinifera lines constitutively expressing the V. riparia E3 ubiquitin ligase gene VriATL156. Phenotypic and molecular analysis revealed that the transgenic plants were less susceptible to P. viticola than vector-only controls, confirming the role of this E3 ubiquitin ligase in the innate immune response. Two independent transgenic lines were selected for detailed analysis of the resistance phenotype by RNA-Seq and microscopy, revealing the profound reprogramming of transcription to achieve resistance that operates from the earliest stages of pathogen infection. The introduction of VriATL156 into elite grapevine cultivars could therefore provide an effective and sustainable control measure against downy mildew. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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18 pages, 3920 KiB

Open AccessArticle

E3 Ubiquitin Ligase APC/C^Cdh1 Regulation of Phenylalanine Hydroxylase Stability and Function

by Apoorvi Tyagi, Neha Sarodaya, Kamini Kaushal, Arun Pandian Chandrasekaran, Ainsley Mike Antao, Bharathi Suresh, Byung Ho Rhie, Kye Seong Kim and Suresh Ramakrishna

Int. J. Mol. Sci. 2020, 21(23), 9076; https://doi.org/10.3390/ijms21239076 - 28 Nov 2020

Cited by 11 | Viewed by 3924

Abstract

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by the dysfunction of the enzyme phenylalanine hydroxylase (PAH). Alterations in the level of PAH leads to the toxic accumulation of phenylalanine in the blood and brain. Protein degradation mediated by ubiquitination is a principal cellular process for maintaining protein homeostasis. Therefore, it is important to identify the E3 ligases responsible for PAH turnover and proteostasis. Here, we report that anaphase-promoting complex/cyclosome-Cdh1 (APC/C)^Cdh1 is an E3 ubiquitin ligase complex that interacts and promotes the polyubiquitination of PAH through the 26S proteasomal pathway. Cdh1 destabilizes and declines the half-life of PAH. In contrast, the CRISPR/Cas9-mediated knockout of Cdh1 stabilizes PAH expression and enhances phenylalanine metabolism. Additionally, our current study demonstrates the clinical relevance of PAH and Cdh1 correlation in hepatocellular carcinoma (HCC). Overall, we show that PAH is a prognostic marker for HCC and Cdh1 could be a potential therapeutic target to regulate PAH-mediated physiological and metabolic disorders. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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17 pages, 10577 KiB

Open AccessArticle

E3 Ubiquitin Ligase APC/C^Cdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination

by Kamini Kaushal, Sang Hyeon Woo, Apoorvi Tyagi, Dong Ha Kim, Bharathi Suresh, Kye-Seong Kim and Suresh Ramakrishna

Int. J. Mol. Sci. 2020, 21(22), 8719; https://doi.org/10.3390/ijms21228719 - 18 Nov 2020

Cited by 3 | Viewed by 2697

Abstract

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in the degradation pathway of the amino acids tyrosine and phenylalanine in mammals that catalyzes the hydrolysis of 4-fumarylacetoacetate into acetoacetate and fumarate. Mutations of the FAH gene are associated with hereditary tyrosinemia type I (HT1), resulting in reduced protein stability, misfolding, accelerated degradation and deficiency in functional proteins. Identifying E3 ligases, which are necessary for FAH protein stability and degradation, is essential. In this study, we demonstrated that the FAH protein level is elevated in liver cancer tissues compared to that in normal tissues. Further, we showed that the FAH protein undergoes 26S proteasomal degradation and its protein turnover is regulated by the anaphase-promoting complex/cyclosome-Cdh1 (APC/C)^Cdh1 E3 ubiquitin ligase complex. APC/C^Cdh1 acts as a negative stabilizer of FAH protein by promoting FAH polyubiquitination and decreases the half-life of FAH protein. Thus, we envision that Cdh1 might be a key factor in the maintenance of FAH protein level to regulate FAH-mediated physiological functions. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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20 pages, 3898 KiB

Open AccessArticle

CDK5RAP3, a Novel Nucleoplasmic Shuttle, Deeply Regulates HSF1-Mediated Heat Stress Response and Protects Mammary Epithelial Cells from Heat Injury

by Yangyang Shen, Yan Zou, Jun Li, Fanghui Chen, Honglin Li and Yafei Cai

Int. J. Mol. Sci. 2020, 21(21), 8400; https://doi.org/10.3390/ijms21218400 - 09 Nov 2020

Cited by 5 | Viewed by 2701

Abstract

CDK5RAP3 was regarded as the most significant regulator of cellular responses against heat stress, which is associated with dysfunctions of the immune system and animal susceptibility to disease. Despite this, little known about how CDK5RAP3 regulates heat stress response. In this study, CDK5RAP3 conditional Knockout (CKO) mice, CDK5RAP3^-/- mouse embryo fibroblasts (MEFs) and bovine mammary epithelial cells (BMECs) were used as an in vitro and in vivo model, respectively to reveal the role of CDK5RAP3 in regulating the heat stress response. The deletion of CDK5RAP3 unexpectedly caused animal lethality after 1.5-h heat stimulations. Furthermore, BMECs were re-cultured for eight hours after heat stress and was found that the expression of CDK5RAP3 and HSPs showed a similar fluctuating pattern of increase (0–2, 4–6 h) and decrease (2–4, 6–8 h). In addition to the remarkably enhanced expression of heat shock protein, apoptosis rate and endoplasmic reticulum stress, the deletion of CDK5RAP3 also affected nucleoplasmic translocation and trimer formation of heat shock factor 1 (HSF1). These programs were further confirmed in the mammary gland of CDK5RAP3 CKO mice and CDK5RAP3^-/- MEFs as well. Interestingly, genetic silencing of HSF1 downregulated CDK5RAP3 expression in BMECs. Immunostaining and immunoprecipitation studies suggested a physical interaction between CDK5RAP3 and HSF1 being co-localized in the cytoplasm and nucleus. Besides, CDK5RAP3 also interacted with HSP90, suggesting an operative machinery at both transcriptional level and protein functionality of HSP90 per se. Together, our findings suggested that CDK5RAP3 works like a novel nucleoplasmic shuttle or molecular chaperone, deeply participating in HSF1-mediated heat stress response and protecting cells from heat injury. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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Review

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17 pages, 990 KiB

Open AccessReview

The Role of E3s in Regulating Pluripotency of Embryonic Stem Cells and Induced Pluripotent Stem Cells

by Yahong Wu and Weiwei Zhang

Int. J. Mol. Sci. 2021, 22(3), 1168; https://doi.org/10.3390/ijms22031168 - 25 Jan 2021

Cited by 2 | Viewed by 3745

Abstract

Pluripotent embryonic stem cells (ESCs) are derived from early embryos and can differentiate into any type of cells in living organisms. Induced pluripotent stem cells (iPSCs) resemble ESCs, both of which serve as excellent sources to study early embryonic development and realize cell replacement therapies for age-related degenerative diseases and other cell dysfunction-related illnesses. To achieve these valuable applications, comprehensively understanding of the mechanisms underlying pluripotency maintenance and acquisition is critical. Ubiquitination modifies proteins with Ubiquitin (Ub) at the post-translational level to monitor protein stability and activity. It is extensively involved in pluripotency-specific regulatory networks in ESCs and iPSCs. Ubiquitination is achieved by sequential actions of the Ub-activating enzyme E1, Ub-conjugating enzyme E2, and Ub ligase E3. Compared with E1s and E2s, E3s are most abundant, responsible for substrate selectivity and functional diversity. In this review, we focus on E3 ligases to discuss recent progresses in understanding how they regulate pluripotency and somatic cell reprogramming through ubiquitinating core ESC regulators. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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24 pages, 8027 KiB

Open AccessReview

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

by Ying Li and David Reverter

Int. J. Mol. Sci. 2021, 22(3), 986; https://doi.org/10.3390/ijms22030986 - 20 Jan 2021

Cited by 34 | Viewed by 4927

Abstract

The large family of deubiquitinating enzymes (DUBs) are involved in the regulation of a plethora of processes carried out inside the cell by protein ubiquitination. Ubiquitination is a basic pathway responsible for the correct protein homeostasis in the cell, which could regulate the fate of proteins through the ubiquitin–proteasome system (UPS). In this review we will focus on recent advances on the molecular mechanisms and specificities found for some types of DUBs enzymes, highlighting illustrative examples in which the regulatory mechanism for DUBs has been understood in depth at the molecular level by structural biology. DUB proteases are responsible for cleavage and regulation of the multiple types of ubiquitin linkages that can be synthesized inside the cell, known as the ubiquitin-code, which are tightly connected to specific substrate functions. We will display some strategies carried out by members of different DUB families to provide specificity on the cleavage of particular ubiquitin linkages. Finally, we will also discuss recent progress made for the development of drug compounds targeting DUB proteases, which are usually correlated to the progress of many pathologies such as cancer and neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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34 pages, 3333 KiB

Open AccessReview

E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

by Manon Brunet, Claire Vargas, Dorian Larrieu, Jérôme Torrisani and Marlène Dufresne

Int. J. Mol. Sci. 2020, 21(22), 8515; https://doi.org/10.3390/ijms21228515 - 12 Nov 2020

Cited by 23 | Viewed by 5094

Abstract

The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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23 pages, 932 KiB

Open AccessReview

Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

by Roya Rasaei, Neha Sarodaya, Kye-Seong Kim, Suresh Ramakrishna and Seok-Ho Hong

Int. J. Mol. Sci. 2020, 21(21), 8090; https://doi.org/10.3390/ijms21218090 - 29 Oct 2020

Cited by 8 | Viewed by 3205

Abstract

Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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13 pages, 2011 KiB

Open AccessReview

The Roles of SPOP in DNA Damage Response and DNA Replication

by Masashi Maekawa and Shigeki Higashiyama

Int. J. Mol. Sci. 2020, 21(19), 7293; https://doi.org/10.3390/ijms21197293 - 02 Oct 2020

Cited by 12 | Viewed by 3715

Abstract

Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of these SPOP mutants, thus, causes aberrant turnovers of the substrate proteins, leading to tumor formation. Although the molecular properties of SPOP and its cancer-associated mutants have been intensively elucidated, their cellular functions remain unclear. Recently, a number of studies have uncovered the critical role of SPOP and its mutants in DNA damage response and DNA replication. In this review article, we summarize the physiological functions of SPOP as a “gatekeeper” of genome stability. Full article

(This article belongs to the Special Issue The Role of E3 Ligases and Deubiquitinating Enzymes in Cellular Signaling, Diseases, and Therapeutics)

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