Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1086870 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We established that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a key step in establishing the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
2024-03-19 | GSE261399 | GEO
Project description:The cooperation of transcriptional and post-transcriptional controls to shape gene regulation is poorly understood. Here we show that a combination of two simple and non-invasive genomic techniques, coupled with kinetic mathematical modelling, afford insight into the multi-layered regulation of gene expression dynamics in response to oxidative stress in the fission yeast Schizosaccharomyces pombe. This study reveals a dominant role of transcriptional control in response to stress, and it points to the first minutes after stress induction as a critical time when control of mRNA turnover can support transcriptional control for rapid gene regulation. In addition, we uncover specialized gene expression strategies such as simultaneous transcriptional repression and mRNA destabilization for genes encoding ribosomal proteins, delayed mRNA destabilization with varying contribution of transcription for the ribosome biogenesis regulon, dominant roles of mRNA stabilisation for genes participating in protein degradation, and adjustment of mRNA turnover during stress adaptation. We also show that genes regulated independently of the Atf1p transcription factor are mainly controlled by mRNA turnover during oxidative stress.
2014-06-01 | E-MTAB-2579 | biostudies-arrayexpress
Project description:The cooperation of transcriptional and post-transcriptional controls to shape gene regulation is poorly understood. Here we show that a combination of two simple and non-invasive genomic techniques, coupled with kinetic mathematical modelling, afford insight into the multi-layered regulation of gene expression dynamics in response to oxidative stress in the fission yeast Schizosaccharomyces pombe. This study reveals a dominant role of transcriptional control in response to stress, and it points to the first minutes after stress induction as a critical time when control of mRNA turnover can support transcriptional control for rapid gene regulation. In addition, we uncover specialized gene expression strategies such as simultaneous transcriptional repression and mRNA destabilization for genes encoding ribosomal proteins, delayed mRNA destabilization with varying contribution of transcription for the ribosome biogenesis regulon, dominant roles of mRNA stabilisation for genes participating in protein degradation, and adjustment of mRNA turnover during stress adaptation. We also show that genes regulated independently of the Atf1p transcription factor are mainly controlled by mRNA turnover during oxidative stress. <br><br>An additional file containing normalized data is available on the FTP site for this experiment.
2013-07-01 | E-MTAB-504 | biostudies-arrayexpress
Project description:To study the contribution of RNA-binding proteins (RBPs) to the regulation of RNA turnover, we used DNA microarrays to examine the transcriptome of S. pombe strains containing deletions in non-essential genes encoding RBPs
2014-11-06 | E-MTAB-2314 | biostudies-arrayexpress
Project description:Protease Encoding bacteria in arable fields
| PRJEB24038 | ENA
Project description:Drought responsiveness dynamics in wheat
| PRJNA686121 | ENA
Project description:We use a metabolic labeling strategy for directly measuring nucleosome turnover to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around gene promoters, and turnover correlates with gene expression level. Keywords: Chromatin affinity-purification on microarray 26 CATCH-IT arrays and 8 expression arrays.
2013-04-19 | E-GEOD-43753 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance. In addition to genetic mutations, recent research has identified a role for non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.
2024-05-22 | GSE247691 | GEO
Project description:Using a recently established histone turnover sensor, we measured the genome-wide H3 turnover during S-phase in S.cerevisiae.
2022-02-18 | GSE193044 | GEO
Project description:<p>Biosynthetic gene clusters (BGCs) encoding the production of bacteriocins are widespread among bacterial isolates and are important genetic determinants of competitive fitness within a given habitat. Staphylococci produce a tremendous diversity of compounds, and the corresponding BGCs are frequently associated with mobile genetic elements, suggesting gain and loss of biosynthetic capacity. Pharmaceutical biology has shown that compound production in heterologous hosts is often challenging, and many BGC recipients initially produce small amounts of compound or show reduced growth rates. To assess whether transfer of BGCs between closely related Staphylococcus aureus strains can be instantly effective or requires elaborate metabolic adaptation, we investigated the intraspecies transfer of a BGC encoding the ribosomally synthesized and posttranslationally modified peptide (RiPP) micrococcin P1 (MP1). We found that acquisition of the BGC by S. aureus RN4220 enabled immediate MP1 production but also imposed a metabolic burden, which was relieved after prolonged cultivation by adaptive mutation. We used a multiomics approach to study this phenomenon and found adaptive evolution to select for strains with increased activity of the tricarboxylic acid cycle (TCA), which enhanced metabolic fitness and levels of compound production. Metabolome analysis revealed increases of central metabolites, including citrate and α-ketoglutarate in the adapted strain, suggesting metabolic adaptation to overcome the BGC-associated growth defects. Our results indicate that BGC acquisition requires genetic and metabolic predispositions, allowing the integration of bacteriocin production into the cellular metabolism. Inappropriate metabolic characteristics of recipients can entail physiological burdens, negatively impacting the competitive fitness of recipients within natural bacterial communities.</p><p><strong>IMPORTANCE:</strong> Human microbiomes are critically associated with human health and disease. Importantly, pathogenic bacteria can hide in human-associated communities and can cause disease when the composition of the community becomes unbalanced. Bacteriocin-producing commensals are able to displace pathogens from microbial communities, suggesting that their targeted introduction into human microbiomes might prevent pathogen colonization and infection. However, to develop probiotic approaches, strains are needed that produce high levels of bioactive compounds and retain cellular fitness within mixed bacterial communities. Our work offers insights into the metabolic burdens associated with the production of the bacteriocin micrococcin P1 and highlights evolutionary strategies that increase cellular fitness in the context of production. Metabolic adaptations are most likely broadly relevant for bacteriocin producers and need to be considered for the future development of effective microbiome editing strategies.</p>
2022-11-09 | MTBLS5196 | MetaboLights