SUMO in the regulation of DNA repair and transcription at nuclear pores DOI Creative Commons
Susan M. Gasser, Françoise Stutz

FEBS Letters, Journal Year: 2023, Volume and Issue: 597(22), P. 2833 - 2850

Published: Oct. 9, 2023

Two related post-translational modifications, the covalent linkage of Ubiquitin and Small Ubiquitin-related MOdifier (SUMO) to lysine residues, play key roles in regulation both DNA repair pathway choice transcription. Whereas ubiquitination is generally associated with proteasome-mediated protein degradation, impact sumoylation has been more mysterious. In cell nucleus, effects are largely mediated by relocalization modified targets, particularly response damage. This governed part concentration SUMO protease at nuclear pores [Melchior, F et al. (2003) Trends Biochem Sci 28, 612-618; Ptak, C Wozniak, RW (2017) Adv Exp Med Biol 963, 111-126]. We review here determining genomic locus positioning relative envelope pores, facilitate regulate

Language: Английский

Deubiquitinases in cancer DOI
Grant Dewson, Pieter J.A. Eichhorn, David Komander

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(12), P. 842 - 862

Published: Nov. 7, 2023

Language: Английский

Citations

126
Extracellular targeted protein degradation: an emerging modality for drug discovery DOI
James A. Wells, Kaan Kumru

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 23(2), P. 126 - 140

Published: Dec. 7, 2023

Language: Английский

Citations

69
Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin DOI Creative Commons
Paweł M. Wydorski,

J. Osipiuk,

Benjamin T. Lanham

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 25, 2023

Abstract The Papain-like protease (PLpro) is a domain of multi-functional, non-structural protein 3 coronaviruses. PLpro cleaves viral polyproteins and posttranslational conjugates with poly-ubiquitin protective ISG15, composed two ubiquitin-like (UBL) domains. Across coronaviruses, showed divergent selectivity for recognition cleavage despite sequence conservation. We show that SARS-CoV-2 binds human ISG15 K48-linked di-ubiquitin (K48-Ub 2 ) nanomolar affinity detect alternate weaker-binding modes. Crystal structures untethered complexes K48-Ub combined solution NMR cross-linking mass spectrometry revealed how the domains or are differently utilized in interactions PLpro. Analysis interface energetics predicted differential binding stabilities UBL/Ub were validated experimentally. emphasize substrate can be tuned to cleave specifically modifications while retaining capacity mono-Ub conjugates. These results highlight alternative druggable surfaces would inhibit function.

Language: Английский

Citations

52
Shared and distinct mechanisms of UBA1 inactivation across different diseases DOI Creative Commons
Jason C. Collins, Samuel J. Magaziner, Maya English

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(10), P. 1919 - 1946

Published: Feb. 15, 2024

Abstract Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little known about the underlying molecular mechanisms. Here, dissecting VEXAS-causing mutations, we discovered that p.Met41 alter cytoplasmic isoform expression, whereas other reduce catalytic activity nuclear isoforms diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 most prominently affect transthioesterification, revealing transfer enzymes as a shared property pathogenesis amongst different syndrome genotypes. A similar charging bottleneck exists in some lung cancer-associated but not spinal muscular atrophy-causing instead, render thermolabile. Collectively, our results highlight precision conformational changes required for faithful transfer, define distinct mechanisms inactivation diseases, suggest specific E1-E2 modules control aspects tissue differentiation maintenance.

Language: Английский

Citations

22
Applications of protein ubiquitylation and deubiquitylation in drug discovery DOI Creative Commons
Yilin Chen, Haoan Xue, Jianping Jin

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107264 - 107264

Published: April 5, 2024

The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS involved many important cellular processes. Several new UPS-based technologies, including molecular glue degraders PROTACs (Proteolysis-targeting chimeras) to promote DUBTACs (deubiquitinase-targeting increase stability, have been developed. specifically inducing interactions between different ubiquitin ligases targeted that are not otherwise related, degrade via system; contrast, by proximity of deubiquitinases, created clear degradable polyubiquitin chains stabilize proteins. In this review, we summarize recent research progress degraders, PROTACs, applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting development PROTACs. also introduce principle DUBTAC its Finally, propose a few future directions these three technologies related homeostasis.

Language: Английский

Citations

21
N-degron pathways DOI Creative Commons
Alexander Varshavsky

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(39)

Published: Sept. 12, 2024

An N-degron is a degradation signal whose main determinant “destabilizing” N-terminal residue of protein. Specific N-degrons, discovered in 1986, were the first identified signals short-lived intracellular proteins. These N-degrons are recognized by ubiquitin-dependent proteolytic system called Arg/N-degron pathway. Although bacteria lack ubiquitin system, they also have pathways. Studies after 1986 shown that all 20 amino acids genetic code can act, specific sequence contexts, as destabilizing residues. Eukaryotic proteins targeted for conditional or constitutive at least five systems differ both functionally and mechanistically: pathway, Ac/N-degron Pro/N-degron fMet/N-degron newly named, this perspective, GASTC/N-degron pathway (GASTC = Gly, Ala, Ser, Thr, Cys). I discuss these expanded terminology now encompasses entire gamut known

Language: Английский

Citations

19
Ubiquitin—A structural perspective DOI
Rashmi Agrata, David Komander

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 323 - 346

Published: Jan. 1, 2025

Language: Английский

Citations

3
The BRUTUS iron sensor and E3 ligase facilitates soybean root nodulation by monoubiquitination of NSP1 DOI
Ziyin Ren, Ling Zhang, Haizhen Li

et al.

Nature Plants, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Language: Английский

Citations

3
Ubiquitination and deubiquitination: Implications on cancer therapy DOI

Gunjan Dagar,

Rakesh Kumar, Kamlesh Yadav

et al.

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Journal Year: 2023, Volume and Issue: 1866(4), P. 194979 - 194979

Published: Aug. 24, 2023

Language: Английский

Citations

42
Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy DOI Creative Commons
Daniela Spano, Giuliana Catara

Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 29 - 29

Published: Dec. 22, 2023

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects various signaling pathways. can alter molecular functions tagged substrates respect protein turnover, biological activity, subcellular localization or protein–protein interaction. As result, wide variety cellular processes are under ubiquitination-mediated control, contributing maintenance homeostasis. It follows that dysregulation ubiquitination reactions plays relevant role in pathogenic states human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, enzymes ubiquitin–proteasome system (UPS), including E3 ligases deubiquitinases (DUBs), have attracted attention novel druggable targets for development new anticancer therapeutic approaches. This perspective article summarizes peculiarities shared by involved reaction which, when deregulated, lead tumorigenesis. Accordingly, an overview main pharmacological interventions targeting UPS clinical use still trials provided, also highlighting limitations efficacy these Therefore, attempts circumvent drug resistance side well UPS-related emerging technologies therapeutics discussed.

Language: Английский

Citations

30