The Ubiquitin Proteasome System in Genome Stability and Cancer

Morgan, Jonathan J.; Crawford, Lisa

doi:10.3390/cancers13092235

Cited by 23 publications

(17 citation statements)

References 125 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Up to now, an approximate number of 100 DUB have been identified, whereby the largest families are represented by the ubiquitin-specific proteases (USP), the ovarian tumor proteases (OTU), and ubiquitin C-terminal hydrolases (UCH) ( Clague et al, 2019 ). Many DUB and E3 ubiquitin ligases regulate fundamental cellular pathways including cell division or death, genomic integrity, epigenetic control, developmental, and differentiation pathways as well as cellular homeostasis ( Morgan and Crawford, 2021 ).…”

Section: The Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Ebstein

Küry

Papendorf

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

show abstract

Section: The Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Ebstein

Küry

Papendorf

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Since tumour cells are characterised by abnormal metabolism, the ubiquitin‐proteasome system (UPS) that mainly functions in intracellular protein turnover is highly active. A paramount example of this problem is the observation that specific inhibitors targeting the UPS represents an effective strategy for cancer therapy 4,5 . The integrated 26S proteasome is comprised of two 19S regulation portions and a core 20S degradation portion.…”

Section: Introductionmentioning

confidence: 99%

“…A paramount example of this problem is the observation that specific inhibitors targeting the UPS represents an effective strategy for cancer therapy. 4 , 5 The integrated 26S proteasome is comprised of two 19S regulation portions and a core 20S degradation portion. Before an ubiquitinated protein is degraded by the proteasome, it should be firstly recruited to 19S portion, where its polyubiquitin chain is removed by 19S proteasomal deubiquitinases, including USP14, UCHL5 and POH1.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Jiang

Chen

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Background Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR‐ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)‐based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR‐ABLT315I. Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin‐proteasome system and possess multiple functions during cancer progression. Methods The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b‐AP15. We explored the effect of b‐AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b‐AP15 on BCR‐ABLWT and BCR‐ABLT315I CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML. Results In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b‐AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour‐killing activity in BCR‐ABLWT and BCR‐ABLT315I CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR‐ABL in CML cells expressing BCR‐ABLWT and BCR‐ABLT315I. Moreover, b‐AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR‐ABLWT and BCR‐ABLT315I CML cells. Conclusion Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.

show abstract

“…In this manner, ubiquitination is a reversible and highly dynamic process within cells, the vast complexities of which we are only beginning to understand ( Yau and Rape, 2016 ). Moreover, given its wide-ranging role in regulating myriad cellular pathways, the ubiquitin system has become a prominent target for drug discovery to treat a range of different pathologies ( Rape, 2018 ; Wu et al, 2020 ; Duan and Pagano, 2021 ; Morgan and Crawford, 2021 ; Tokheim et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Tools for Decoding Ubiquitin Signaling in DNA Repair

Foster

Attwood

Gibbs-Seymour

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The maintenance of genome stability requires dedicated DNA repair processes and pathways that are essential for the faithful duplication and propagation of chromosomes. These DNA repair mechanisms counteract the potentially deleterious impact of the frequent genotoxic challenges faced by cells from both exogenous and endogenous agents. Intrinsic to these mechanisms, cells have an arsenal of protein factors that can be utilised to promote repair processes in response to DNA lesions. Orchestration of the protein factors within the various cellular DNA repair pathways is performed, in part, by post-translational modifications, such as phosphorylation, ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs). In this review, we firstly explore recent advances in the tools for identifying factors involved in both DNA repair and ubiquitin signaling pathways. We then expand on this by evaluating the growing repertoire of proteomic, biochemical and structural techniques available to further understand the mechanistic basis by which these complex modifications regulate DNA repair. Together, we provide a snapshot of the range of methods now available to investigate and decode how ubiquitin signaling can promote DNA repair and maintain genome stability in mammalian cells.

show abstract

The Ubiquitin Proteasome System in Genome Stability and Cancer

Cited by 23 publications

References 125 publications

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Tools for Decoding Ubiquitin Signaling in DNA Repair

Contact Info

Product

Resources

About