Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA317531 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3340650_1.fastq.gz | Fastqsanger.gz | |||
| SRR3340650_2.fastq.gz | Fastqsanger.gz | |||
| SRR3340660_1.fastq.gz | Fastqsanger.gz | |||
| SRR3340660_2.fastq.gz | Fastqsanger.gz | |||
| SRR3340651_1.fastq.gz | Fastqsanger.gz |
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Project description:ATXN7L3 And ENY2 Coordinate Activity Of Multiple H2B Deubiquitinases Important For Cellular Proliferation And Tumor Growth
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Project description:he Mpr1/Pad1 N-terminal domain-containing protein (MPND) belongs to the JAMM family of deubiquitinases and is ubiquitously expressed across human tissues. However, its role in non-small cell lung cancer (NSCLC) remains unexplored. In this study, we demonstrate that MPND expression is frequently reduced in NSCLC, and that low levels of MPND correlate with poor clinical outcomes. Depletion of MPND in vitro enhances cell migration, invasion, and cancer stem cell (CSC)-like characteristics in NSCLC cells. Mechanistically, MPND interacts with histones, removing ubiquitin from H2A K119 monoubiquitination (H2A K119ub) and H2B K120 monoubiquitination (H2B K120ub). Loss of MPND elevates these ubiquitination marks, leading to alterations in chromatin architecture. Furthermore, MPND influences gene transcription, and its depletion activates the TGF-beta/SMAD3 signaling pathway. Specifically, knockout of MPND increases H2B K120 ubiquitination and chromatin accessibility at the SMAD3 locus, facilitating its transcriptional activation. Using mouse tumor models and clinical samples from NSCLC patients, we show that loss of MPND triggers activation of the TGF-beta/SMAD3 axis, thereby promoting tumor growth and metastasis. Collectively, these findings deepen our understanding of the epigenetic mechanisms underlying NSCLC progression and suggest that anti-TGF-beta therapies may be particularly beneficial for treating MPND-deficient tumors.
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Project description:This model is from the article:
A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction.
Watterson S, Guerriero ML, Blanc M, Mazein A, Loewe L, Robertson KA, Gibbs H, Shui G, Wenk MR, Hillston J, Ghazal P. Biochimie.
2012 Jun 1. 22664637
,
Abstract:
The cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalysing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses.
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Project description:Histone modifications perform a vast array of functions in regulating gene expression, DNA replication, and repair. Monoubiquitination of histone H2B at K123 in yeast (K120 in humans) is an intriguing modification because it is deposited cotranscriptionally, mediates the installation of several other epigenetic marks, and then disappears; hence, it is associated transiently with actively transcribed chromatin. In yeast, the H2B ubiquitin writer is the E2/E3 pair Rad6/Bre1, and there are two deubiquitinases that can erase it, Ubp8 and Ubp10. Whilst Ubp8 resides within the larger SAGA complex, Ubp10 (USP36 in humans) is a monomeric and constitutively active deubiquitinase, raising questions as to what processes regulate it, given it would be undesirable for H2B to be deubiquitinated prematurely before downstream processes connected to this epigenetic mark occur. Here we show that Ubp10’s activity is regulated by acidic regions within its long N-terminal intrinsically disordered region (IDR), which extensively interact with H2A/H2B dimers, as shown by crosslinking mass spectrometry. These interactions vanish when H2A/H2B is present in nucleosomes. These observations explain why Ubp10 has low baseline activity on nucleosomes, but is activated by FACT, a histone chaperone which evicts H2A/H2B dimers from nucleosomes, thereby generating Ubp10’s preferred substrate, which we demonstrate with single molecule fluorescence experiments. Hence, this work provides a biophysical mechanism for how Ubp10 can provide a housekeeping function to deubiquitinate actively-transcribed DNA, wherein FACT produces a temporary pool of H2A/H2B dimers.
2025-07-16 | PXD051971 | Pride
Project description:Light is a crucial exogenous signal sensed by cryptochrome (CRY) blue light receptors to modulate growth and the circadian clock in plants and animals. However, how CRYs interpret light quantity to regulate growth in plants remains poorly understood. Furthermore, CRY2 protein levels and activity are tightly regulated in light to fine-tune hypocotyl growth; however, details of the mechanisms that explain precise control of CRY2 levels are not fully understood. We show that in Arabidopsis, UBP12 and UBP13 deubiquitinases physically interact with CRY2 in light. UBP12/13 negatively regulates CRY2 by promoting its ubiquitination and turnover to modulate hypocotyl growth. Growth and development were explicitly affected in blue light when UBP12/13 were disrupted or overexpressed, indicating their role alongside CRY2. UBP12/13 also interacted with and stabilized COP1, which is partially required for CRY2 turnover. Our combined genetic and molecular data support a mechanistic model in which UBP12/13 interact with CRY2 and COP1, leading to the stabilization of COP1. Stabilized COP1 then promotes the ubiquitination and degradation of CRY2 under blue light. Despite decades of studies on deubiquitinases, the knowledge of how their activity is regulated is limited. Our study provides insight into how exogenous signals and ligands, along with their receptors, regulate deubiquitinase activity by protein-protein interaction. Collectively, our results provide a framework of cryptochromes and deubiquitinases to detect and interpret light signals to control plant growth at the most appropriate time.
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