Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Reversible and rapid transfer-RNA deactivation as a mechanism of translational repression in stress.

ABSTRACT: Stress-induced changes of gene expression are crucial for survival of eukaryotic cells. Regulation at the level of translation provides the necessary plasticity for immediate changes of cellular activities and protein levels. In this study, we demonstrate that exposure to oxidative stress results in a quick repression of translation by deactivation of the aminoacyl-ends of all transfer-RNA (tRNA). An oxidative-stress activated nuclease, angiogenin, cleaves first within the conserved single-stranded 3'-CCA termini of all tRNAs, thereby blocking their use in translation. This CCA deactivation is reversible and quickly repairable by the CCA-adding enzyme [ATP(CTP):tRNA nucleotidyltransferase]. Through this mechanism the eukaryotic cell dynamically represses and reactivates translation at low metabolic costs.

SUBMITTER: Czech A

PROVIDER: S-EPMC3757041 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Reversible and rapid transfer-RNA deactivation as a mechanism of translational repression in stress.

Czech Andreas A Wende Sandra S Mörl Mario M Pan Tao T Ignatova Zoya Z

PLoS genetics 20130829 8

Stress-induced changes of gene expression are crucial for survival of eukaryotic cells. Regulation at the level of translation provides the necessary plasticity for immediate changes of cellular activities and protein levels. In this study, we demonstrate that exposure to oxidative stress results in a quick repression of translation by deactivation of the aminoacyl-ends of all transfer-RNA (tRNA). An oxidative-stress activated nuclease, angiogenin, cleaves first within the conserved single-stran ...[more]

PMID: 24009533

Similar Datasets

Translational repression by RNA-binding protein TIAR.

Project description:The RNA-binding protein TIAR has been proposed to inhibit protein synthesis transiently by promoting the formation of translationally silent stress granules. Here, we report the selective binding of TIAR to several mRNAs encoding translation factors such as eukaryotic initiation factor 4A (eIF4A) and eIF4E (translation initiation factors), eEF1B (a translation elongation factor), and c-Myc (which transcriptionally controls the expression of numerous translation regulatory proteins). TIAR bound the 3'-untranslated regions of these mRNAs and potently suppressed their translation, particularly in response to low levels of short-wavelength UV (UVC) irradiation. The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression. We propose that the TIAR-mediated inhibition of translation factor expression elicits a sustained repression of protein biosynthesis in cells responding to stress.

| S-EPMC1430315 | biostudies-literature

Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation.

Project description:Resistance to chemotherapy drugs is a serious therapeutic problem and its underlying molecular mechanisms are complex. Stress granules (SGs), cytoplasmic ribonucleoprotein complexes assembled in cells exposed to stress, are implicated in various aspects of cancer cell metabolism and survival. SGs promote the survival of stressed cells by reprogramming gene expression and inhibiting pro-apoptotic signaling cascades. We show that the vinca alkaloid (VA) class of anti-neoplastic agents potently activates a SG-mediated stress response program. VAs inhibit translation initiation by simultaneous activation of eIF4E-BP1 and phosphorylation of eIF2α, causing polysome disassembly and SG assembly. VA-induced SGs contain canonical SG components but lack specific signaling molecules. Blocking VA-induced SG assembly by inactivating eIF4EBP1 or inhibiting eIF2α phosphorylation decreases cancer cell viability and promotes apoptosis. Our data describe previously unappreciated effects of VAs on cellular RNA metabolism and illuminate the roles of SGs in cancer cell survival.

| S-EPMC5058682 | biostudies-literature

Puf3p induces translational repression of genes linked to oxidative stress.

Project description:In response to stress, the translation of many mRNAs in yeast can change in a fashion discordant with the general repression of translation. Here, we use machine learning to mine the properties of these mRNAs to determine specific translation control signals. We find a strong association between transcripts acutely translationally repressed under oxidative stress and those associated with the RNA-binding protein Puf3p, a known regulator of cellular mRNAs encoding proteins targeted to mitochondria. Under oxidative stress, a PUF3 deleted strain exhibits more robust growth than wild-type cells and the shift in translation from polysomes to monosomes is attenuated, suggesting puf3Δ cells perceive less stress. In agreement, the ratio of reduced:oxidized glutathione, a major antioxidant and indicator of cellular redox state, is increased in unstressed puf3Δ cells but remains lower under stress. In untreated conditions, Puf3p migrates with polysomes rather than ribosome-free fractions, but this is lost under stress. Finally, reverse transcriptase-polymerase chain reaction (RT-PCR) of Puf3p targets following affinity purification shows Puf3p-mRNA associations are maintained or increased under oxidative stress. Collectively, these results point to Puf3p acting as a translational repressor in a manner exceeding the global translational response, possibly by temporarily limiting synthesis of new mitochondrial proteins as cells adapt to the stress.

| S-EPMC3902938 | biostudies-literature

PEPseq quantifies transcriptome-wide changes in protein occupancy and reveals selective translational repression after translational stress.

Project description:Post-transcriptional gene regulation is accomplished by the interplay of the transcriptome with RNA-binding proteins, which occurs in a dynamic manner in response to altered cellular conditions. Recording the combined occupancy of all proteins binding to the transcriptome offers the opportunity to interrogate if a particular treatment leads to any interaction changes, pointing to sites in RNA that undergo post-transcriptional regulation. Here, we establish a method to monitor protein occupancy in a transcriptome-wide fashion by RNA sequencing. To this end, peptide-enhanced pull-down for RNA sequencing (or PEPseq) uses metabolic RNA labelling with 4-thiouridine (4SU) for light-induced protein-RNA crosslinking, and N-hydroxysuccinimide (NHS) chemistry to isolate protein-crosslinked RNA fragments across all long RNA biotypes. We use PEPseq to investigate changes in protein occupancy during the onset of arsenite-induced translational stress in human cells and reveal an increase of protein interactions in the coding region of a distinct set of mRNAs, including mRNAs coding for the majority of cytosolic ribosomal proteins. We use quantitative proteomics to demonstrate that translation of these mRNAs remains repressed during the initial hours of recovery after arsenite stress. Thus, we present PEPseq as a discovery platform for the unbiased investigation of post-transcriptional regulation.

| S-EPMC10415142 | biostudies-literature

microRNA-mediated messenger RNA deadenylation contributes to translational repression in mammalian cells.

Project description:Animal microRNAs (miRNAs) typically regulate gene expression by binding to partially complementary target sites in the 3' untranslated region (UTR) of messenger RNA (mRNA) reducing its translation and stability. They also commonly induce shortening of the mRNA 3' poly(A) tail, which contributes to their mRNA decay promoting function. The relationship between miRNA-mediated deadenylation and translational repression has been less clear. Using transfection of reporter constructs carrying three imperfectly matching let-7 target sites in the 3' UTR into mammalian cells we observe rapid target mRNA deadenylation that precedes measureable translational repression by endogenous let-7 miRNA. Depleting cells of the argonaute co-factors RCK or TNRC6A can impair let-7-mediated repression despite ongoing mRNA deadenylation, indicating that deadenylation alone is not sufficient to effect full repression. Nevertheless, the magnitude of translational repression by let-7 is diminished when the target reporter lacks a poly(A) tail. Employing an antisense strategy to block deadenylation of target mRNA with poly(A) tail also partially impairs translational repression. On the one hand, these experiments confirm that tail removal by deadenylation is not strictly required for translational repression. On the other hand they show directly that deadenylation can augment miRNA-mediated translational repression in mammalian cells beyond stimulating mRNA decay. Taken together with published work, these results suggest a dual role of deadenylation in miRNA function: it contributes to translational repression as well as mRNA decay and is thus critically involved in establishing the quantitatively appropriate physiological response to miRNAs.

| S-EPMC2728509 | biostudies-literature

Decoupling Yeast Cell Division and Stress Defense Implicates mRNA Repression in Translational Reallocation during Stress.

Project description:Stress tolerance and rapid growth are often competing interests in cells. Upon severe environmental stress, many organisms activate defense systems concurrent with growth arrest. There has been debate as to whether aspects of the stress-activated transcriptome are regulated by stress or an indirect byproduct of reduced proliferation. For example, stressed Saccharomyces cerevisiae cells mount a common gene expression program called the environmental stress response (ESR) [1] comprised of ∼300 induced (iESR) transcripts involved in stress defense and ∼600 reduced (rESR) mRNAs encoding ribosomal proteins (RPs) and ribosome biogenesis factors (RiBi) important for division. Because ESR activation also correlates with reduced growth rate in nutrient-restricted chemostats and prolonged G1 in slow-growing mutants, an alternate proposal is that the ESR is simply a consequence of reduced division [2-5]. A major challenge is that past studies did not separate effects of division arrest and stress defense; thus, the true responsiveness of the ESR-and the purpose of stress-dependent rESR repression in particular-remains unclear. Here, we decoupled cell division from the stress response by following transcriptome, proteome, and polysome changes in arrested cells responding to acute stress. We show that the ESR cannot be explained by changes in growth rate or cell-cycle phase during stress acclimation. Instead, failure to repress rESR transcripts reduces polysome association of induced transcripts, delaying production of their proteins. Our results suggest that stressed cells alleviate competition for translation factors by removing mRNAs and ribosomes from the translating pool, directing translational capacity toward induced transcripts to accelerate protein production.

| S-EPMC6132260 | biostudies-literature

YB-1 regulates tiRNA-induced Stress Granule formation but not translational repression.

Project description:Stress-induced angiogenin (ANG)-mediated tRNA cleavage promotes a cascade of cellular events that starts with production of tRNA-derived stress-induced RNAs (tiRNAs) and culminates with enhanced cell survival. This stress response program relies on a subset tiRNAs that inhibit translation initiation and induce the assembly of stress granules (SGs), cytoplasmic ribonucleoprotein complexes with cytoprotective and pro-survival properties. SG-promoting tiRNAs bear oligoguanine motifs at their 5'-ends, assemble G-quadruplex-like structures and interact with the translational silencer YB-1. We used CRISPR/Cas9-based genetic manipulations and biochemical approaches to examine the role of YB-1 in tiRNA-mediated translational repression and SG assembly. We found that YB-1 directly binds to tiRNAs via its cold shock domain. This interaction is required for packaging of tiRNA-repressed mRNAs into SGs but is dispensable for tiRNA-mediated translational repression. Our studies reveal the functional role of YB-1 in the ANG-mediated stress response program.

| S-EPMC5001593 | biostudies-literature

Translational repression by deadenylases.

Project description:The CCR4-CAF1-NOT complex is a major cytoplasmic deadenylation complex in yeast and mammals. This complex associates with RNA-binding proteins and microRNAs to repress translation of target mRNAs. We sought to determine how CCR4 and CAF1 participate in repression and control of maternal mRNAs using Xenopus laevis oocytes. We show that Xenopus CCR4 and CAF1 enzymes are active deadenylases and repress translation of an adenylated mRNA. CAF1 also represses translation independent of deadenylation. The deadenylation-independent repression requires a 5' cap structure on the mRNA; however, deadenylation does not. We suggest that mere recruitment of CAF1 is sufficient for repression, independent of deadenylation.

| S-EPMC2937876 | biostudies-literature

Bioactive Peptide Brush Polymers via Photoinduced Reversible-Deactivation Radical Polymerization.

Project description:Harnessing metal-free photoinduced reversible-deactivation radical polymerization (photo-RDRP) in organic and aqueous phases, we report a synthetic approach to enzyme-responsive and pro-apoptotic peptide brush polymers. Thermolysin-responsive peptide-based polymeric amphiphiles assembled into spherical micellar nanoparticles that undergo a morphology transition to worm-like micelles upon enzyme-triggered cleavage of coronal peptide sidechains. Moreover, pro-apoptotic polypeptide brushes show enhanced cell uptake over individual peptide chains of the same sequence, resulting in a significant increase in cytotoxicity to cancer cells. Critically, increased grafting density of pro-apoptotic peptides on brush polymers correlates with increased uptake efficiency and concurrently, cytotoxicity. The mild synthetic conditions afforded by photo-RDRP, make it possible to access well-defined peptide-based polymer bioconjugate structures with tunable bioactivity.

| S-EPMC7299178 | biostudies-literature

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression.

Project description:Expansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

| S-EPMC7335171 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data