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PROVIDER: PRJNA1164421 | ENA |
REPOSITORIES: ENA
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Project description:We established an assay to localize DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map we describe here ties proteolysis to active enhancer elements and to transcription start sites of specific gene families. ChIP-sequencing of ubiquitin and transcription factors was performed in the presence or absence of proteasome inhibition.
2013-12-01 | E-GEOD-33821 | biostudies-arrayexpress
Project description:The ubiquitin proteasome system plays an important role in the pathophysiology of Multiple Myeloma, highlighted by the unique success of proteasome inhibitors in this malignancy. Using topic-defined microarrays we have looked at expression of ubiquitin proteasome system genes in 2 multiple myeloma cell lines and normal bone marrow samples.
2016-10-31 | GSE78884 | GEO
Project description:Proctor2007 - Age related decline of proteolysis, ubiquitin-proteome system
This
is a stochastic model of the ubiquitin-proteasome system for a
generic pool of native proteins (NatP), which have a half-life of
about 10 hours under normal conditions. It is assumed that these
proteins are only degraded after they have lost their native
structure due to a damage event. This is represented in the model
by the misfolding reaction which depends on the level of reactive
oxygen species (ROS) in the cell. Misfolded proteins (MisP) are
first bound by an E3 ubiquitin ligase. Ubiquitin (Ub) is
activated by E1 (ubiquitin-activating enzyme) and then passed to
E2 (ubiquitin-conjugating enzyme). The E2 enzyme then passes the
ubiquitin molecule to the E3/MisP complex with the net effect
that the misfolded protein is monoubiquitinated and both E2 and
E3 are released. Further ubiquitin molecules are added in a
step-wise manner. When the chain of ubiquitin molecules is of
length 4 or more, the polyubiquitinated misfolded protein may
bind to the proteasome. The model also includes de-ubiquitinating
enzymes (DUB) which cleave ubiquitin molecules from the chain in
a step-wise manner. They work on chains attached to misfolded
proteins both unbound and bound to the proteasomes. Misfolded
proteins bound to the proteasome may be degraded releasing
ubiquitin. Misfolded proteins including ubiquitinated proteins
may also aggregate. Aggregates (AggP) may be sequestered
(Seq_AggP) which takes them out of harm's way or they may bind to
the proteasome (AggP_Proteasome). Proteasomes bound by aggregates
are no longer available for protein degradation.
Figure
2 and Figure 3 has been simulated using Gillespie2.
This model is described in the article:
An in silico model of the
ubiquitin-proteasome system that incorporates normal
homeostasis and age-related decline.
Proctor CJ, Tsirigotis M, Gray
DA.
BMC Syst Biol 2007; 1: 17
Abstract:
BACKGROUND: The ubiquitin-proteasome system is responsible
for homeostatic degradation of intact protein substrates as
well as the elimination of damaged or misfolded proteins that
might otherwise aggregate. During ageing there is a decline in
proteasome activity and an increase in aggregated proteins.
Many neurodegenerative diseases are characterised by the
presence of distinctive ubiquitin-positive inclusion bodies in
affected regions of the brain. These inclusions consist of
insoluble, unfolded, ubiquitinated polypeptides that fail to be
targeted and degraded by the proteasome. We are using a systems
biology approach to try and determine the primary event in the
decline in proteolytic capacity with age and whether there is
in fact a vicious cycle of inhibition, with accumulating
aggregates further inhibiting proteolysis, prompting
accumulation of aggregates and so on. A stochastic model of the
ubiquitin-proteasome system has been developed using the
Systems Biology Mark-up Language (SBML). Simulations are
carried out on the BASIS (Biology of Ageing e-Science
Integration and Simulation) system and the model output is
compared to experimental data wherein levels of ubiquitin and
ubiquitinated substrates are monitored in cultured cells under
various conditions. The model can be used to predict the
effects of different experimental procedures such as inhibition
of the proteasome or shutting down the enzyme cascade
responsible for ubiquitin conjugation. RESULTS: The model
output shows good agreement with experimental data under a
number of different conditions. However, our model predicts
that monomeric ubiquitin pools are always depleted under
conditions of proteasome inhibition, whereas experimental data
show that monomeric pools were depleted in IMR-90 cells but not
in ts20 cells, suggesting that cell lines vary in their ability
to replenish ubiquitin pools and there is the need to
incorporate ubiquitin turnover into the model. Sensitivity
analysis of the model revealed which parameters have an
important effect on protein turnover and aggregation kinetics.
CONCLUSION: We have developed a model of the
ubiquitin-proteasome system using an iterative approach of
model building and validation against experimental data. Using
SBML to encode the model ensures that it can be easily modified
and extended as more data become available. Important aspects
to be included in subsequent models are details of ubiquitin
turnover, models of autophagy, the inclusion of a pool of
short-lived proteins and further details of the aggregation
process.
This model is hosted on
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BIOMD0000000105.
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2024-09-02 | BIOMD0000000105 | BioModels
Project description:Bearing in mind the prevalent occurrence of sulfur deficiency in soils, it is highly essential to comprehend the molecular processes of plant response to the changing conditions of sulfur nutrition. As there is an increasing understanding of ubiquitin-proteasomal protein degradation system participation in nutrient deficiency response, we could predict its input to the sulfur metabolism as well. Therefore, we decided to investigate the consequences of proteasome malfunction in Arabidopsis in sulfur deficient conditions. This study presents the transcriptomic response profiles of sulfur-deficient rosettes and roots of Arabidopsis thaliana mutant plants with proteasomal malfunction.
2020-06-09 | GSE137728 | GEO
Project description:<p>We derived faithful cancer cell lines from patients with a diagnosis of renal medullary carcinomas (RMC). These models have been sequenced with whole genome, exome and transcriptome technologies along with the patient's primary germline and tumor samples. We took these faithful models and performed loss-of-function genetic perturbation screens (e.g. RNAi and CRISPR-Cas9) along with an orthogonal small molecule screen. We identified the ubiquitin-proteasome system as an important target in RMC as well as other SMARCB1 deficient cancers.</p>
| phs001800 | dbGaP
Project description:We established an assay to localize DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map we describe here ties proteolysis to active enhancer elements and to transcription start sites of specific gene families.
2013-12-01 | GSE33821 | GEO
Project description:The rare genetic disease Cockayne syndrome (CS) results in mutations in CSA and CSB. Upon UV irradiation, RNA synthesis was arrested: RNA-seq showed 70% of down-regulated genes in common between CSA and CSB deficient cells. ATF3, the product of an immediate early gene was overexpressed and bound to its CRE/ATF site to inhibit its responsive genes. ChIP experiments showed that CSA/CUL4A/DDB1 together with CSB and MDM2, target ATF3. In vivo and in vitro experiments showed that ATF3 was ubiquitilated by a concerted action of CSA and MDM2 ubiquitin-ligases and was further eliminated by the proteasome concomitantly with the recruitment of RNA polymerase II to restart transcription. In CS cells, dysfunctional CSA or CSB were unable to assemble the ubiquitin/proteasome complex, thereby maintaining the ATF3-dependent transcription arrested. Though, in addition to their function in DNA repair, CSA and CSB might thus regulate the timing of DNA binding factors on its specific target site via the ubiquitin/proteasome machinery.
2017-12-01 | GSE87562 | GEO
Project description:The protein ubiquitylation is under the equilibrium between ubiquitin conjugation and deconjugation. How substrates stabilized by deubiquitylation are directed for degradation remains unclear. Branched ubiquitin chains promote substrate degradation through the proteasome, but the underlying mechanisms are not fully understood. TRIP12 and UBR5 are HECT-type E3s specific for the K29 and K48 linkages, respectively. Here, we show that the deubiquitylase (DUB) OTUD5 is cooperatively modified by TRIP12 and UBR5, resulting in the conjugation of K29/K48 branched ubiquitin chains and accelerated proteasomal degradation. The TRIP12–OTUD5 antagonism regulates TNF-–induced NF-B signaling. Mechanistically, although OTUD5 readily cleaves K48 linkages, K29 linkages are resistant against OTUD5 activity. Consequently, K29 linkages overcome OTUD5 DUB activity to facilitate UBR5-dependent K48-linked chain branching. This mechanism is applicable to other TRIP12 substrates associated with OTUD5. These results reveal a unique cellular strategy in which the combination of DUB-resistant and proteasome-targeting ubiquitin linkages efficiently promotes the degradation of substrates protected by deubiquitylation, underscoring the role of branched ubiquitin chains in shifting the ubiquitin conjugation/deconjugation equilibrium.
2025-02-19 | GSE286567 | GEO
Project description:MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand the inferred role of TDMD in shaping miRNA levels in bilaterian animals.
2020-12-18 | GSE163393 | GEO