scholarly journals The Ubiquitin-Proteasome System and DNA Repair

10.5772/24431 ◽  
2011 ◽  
Author(s):  
Christine A. ◽  
Emily C. ◽  
Sumita Raha ◽  
Tatjana Paunesku ◽  
Gayle E.
Keyword(s):  
Dna Repair ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 2: transcriptional regulation

2009 ◽  
Vol 13 (9b) ◽  
pp. 3019-3031 ◽  
Author(s):  
Panagiotis J. Vlachostergios ◽  
Anna Patrikidou ◽  
Danai D. Daliani ◽  
Christos N. Papandreou
Keyword(s):  
Dna Repair ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Major Player ◽  
Ubiquitin Proteasome

scholarly journals Spermatoproteasome-deficient mice are proficient in meiotic DNA repair but defective in meiotic exit

2018 ◽  
Author(s):  
Laura Gómez-H ◽  
Natalia Felipe-Medina ◽  
Yazmine B. Condezo ◽  
Rodrigo Garcia-Valiente ◽  
Isabel Ramos ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genetic Analysis ◽  
Synaptonemal Complex ◽  
Meiotic Recombination ◽  
Ubiquitin Proteasome System ◽  
Crossing Over ◽  
Structural Framework ◽  
Early Spermatid ◽  
Ubiquitin Proteasome ◽  
Deficient Mice

AbstractMeiotic recombination generates crossovers which are essential to ensure genome haploidization. The ubiquitin proteasome system regulates meiotic recombination through its association to the synaptonemal complex, a ‘zipper’-like structure that holds homologs and provides the structural framework for meiotic recombination. Here we show that the testis-specific α4s subunit (PSMA8) of the spermatoproteasome is located at the synaptonemal complex and is essential for the assembly of its activator PA200. Accordingly, synapsis-deficient mice show delocalization of PSMA8 from the synaptonemal complex. Genetic analysis of Psma8-deficient mice shows normal meiotic DNA repair, crossing over formation and an increase of spermatocytes at metaphase I and metaphase II which either enter into apoptosis or slip to give rise to an early spermatid arrest and infertility. Thus, spermatoproteasome-dependent histone degradation is dispensable for meiotic recombination. We show that PSMA8 deficiency alters the proteostasis of several key meiotic players such as acetylated histones, SYCP3, SYCP1, CDK1 and TRIP13 which in turn leads to an aberrant meiotic exit and early spermatid arrest prior to the histone displacement process that take place subsequently.

scholarly journals The Deubiquitylating Enzyme Ubp12 Regulates Rad23-Dependent Substrate Delivery at the Proteasome

2017 ◽  
Author(s):  
Daniela Gödderz ◽  
Nico P. Dantuma
Keyword(s):  
Dna Repair ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Misfolded Proteins ◽  
Proteotoxic Stress ◽  
Lysine Residues ◽  
Regulatory Link ◽  
Ubiquitin Proteasome ◽  
Summary Statement

AbstractThe consecutive actions of the ubiquitin-selective segregase Cdc48 and the ubiquitin shuttle factor Rad23 result in the delivery of ubiquitylated proteins at the proteasome. Here, we show that the deubiquitylating enzyme Ubp12 interacts with Cdc48 and regulates proteasomal degradation of Rad23-dependent substrates. Overexpression of Ubp12 results in stabilization of Rad23-dependent substrates. We show that Ubp12 removes short ubiquitin chains from the N-terminal ubiquitin-like domain (UbL) of Rad23. Preventing ubiquitylation of Rad23 by substitution of lysine residues within the UbL domain, Rad23UbLK0, does not affect the non-proteolytic role of Rad23 in DNA repair but causes an increase in ubiquitylated cargo bound to the UBA2 domains of Rad23 and recapitulates the stabilization of Rad23-dependent substrates observed upon overexpression of Ubp12. Expression of Rad23UbLK0or overexpression of Ubp12 impairs the ability of yeast to cope with proteotoxic stress consistent with inefficient clearance of misfolded proteins by the ubiquitin/proteasome system. Our data suggest that ubiquitylation of Rad23 plays a stimulatory role in facilitating the transfer of ubiquitylated substrates to the proteasome.Summary statementUbiquitylation of a ubiquitin shuttle factor regulates the delivery of substrates at the proteasome, uncovering a novel regulatory link between ubiquitin and proteasomal degradation.

scholarly journals The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 1: post-translational regulation

2009 ◽  
Vol 13 (9b) ◽  
pp. 3006-3018 ◽  
Author(s):  
Panagiotis J. Vlachostergios ◽  
Anna Patrikidou ◽  
Danai D. Daliani ◽  
Christos N. Papandreou
Keyword(s):  
Dna Repair ◽  
Translational Regulation ◽  
Ubiquitin Proteasome System ◽  
Major Player ◽  
Ubiquitin Proteasome

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

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