MRNA regulation by tRNA synthetase through an anticodon mimic
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ABSTRACT:
PROVIDER: PRJEB30963 | ENA |
REPOSITORIES: ENA
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Project description:The Synthetase Sequestration Model (SSM) is a simplified translation model that considers explicitly two main steps in the process of tRNA aminoacylation: first, the tRNA is bound by the aminoacyl tRNA synthetase, and in a second step, the amino acid is attached to the tRNA. The tRNA then participates in the translation reaction, becoming deacylated as a result. The tRNA exists in states bound, charged and uncharged. In the bound state, the tRNA is bound to the synthetase but uncharged, i.e., the tRNA is sequestered by the synthetase. The model predicts how the balance between the three different tRNA states (empty, bound and charged) changes depending on aminoacyl tRNA synthetase availability.
2020-02-05 | MODEL2001080005 | BioModels
Project description:Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging
| PRJNA593256 | ENA
Project description:Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.
2023-06-09 | GSE155309 | GEO
Project description:Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase
| PRJEB41037 | ENA
Project description:An orthogonal aminoacyl-tRNA synthetase/tRNA pair is a key prerequisite for site-specific incorporation of unnatural amino acids. Due to its high codon suppression efficiency and full orthogonality, the pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pair is currently the ideal system for genetic code expansion in both eukaryotes and prokaryotes. There is a pressing need to discover or engineer other fully orthogonal translation systems that allow unnatural amino acids with distinct scaffolds and functionalities to be incorporated into a wide range of living organisms efficiently. Here, through rational chimera design by transplanting the key orthogonal components from the pyrrolysine system, we create multiple chimeric tRNA synthetase/chimeric tRNA pairs, including chimera histidine, phenylalanine, and alanine systems. We further show that these engineered chimeric systems are orthogonal and highly efficient with comparable flexibility to the pyrrolysine system. In addition, the chimera phenylalanine system can incorporate a group of phenylalanine, tyrosine and tryptophan analogues efficiently in both E. coli and mammalian cells. These aromatic amino acids analogous exhibit unique properties and characteristics, including fluorescence, post-translation modification. To our knowledge, most of these molecules have never been shown to be incorporated with fully orthogonal pairs. Therefore, these chimera pairs offer the potential for incorporation of de novo unnatural amino acids into target proteins for a variety of applications.
2020-05-25 | PXD018660 | Pride
Project description:Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic target for CMT.
2019-10-01 | GSE125311 | GEO
Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.
2021-09-07 | GSE160584 | GEO
Project description:During mRNA translation, tRNAs are charged by aminoacyl-tRNA synthetases (aaRS) and subsequently used by ribosomes. A multi-enzyme aminoacyl-tRNA synthetase complex (MSC) has long been proposed to increase protein synthesis efficiency by passing charged tRNAs directly to ribosomes. An alternative is that the MSC repurposes specific synthetases for ex-translational functions that are activated by cues that direct specific enzymes to novel targets. To explore this question, we generated mammalian cell clones in which ArgRS and GlnRS were absent from the MSC to give a stable complex lacking the two enzymes (MSCΔRQ). Protein synthesis, under a variety of stress conditions, was unchanged in MSCΔRQ cells. Most strikingly, levels of charged tRNAGln and tRNAArg remained unchanged and no ribosome pausing was observed at codons for Arg and Gln. Thus, increasing or regulating protein synthesis efficiency is not dependent on ArgRS and GlnRS in the MSC. Alternatively, and consistent with previously reported ex-translational roles, we found manipulations that do not affect protein synthesis but instead MSC cellular localization.
2020-12-23 | PXD021527 | Pride
Project description:RNA immunoprecipitation and sequencing of aminoacyl-tRNA synthetase-specific genes
| PRJNA492296 | ENA
Project description:During mRNA translation, tRNAs are charged by aminoacyl-tRNA synthetases (aaRS) and subsequently used by ribosomes. A multi-enzyme aminoacyl-tRNA synthetase complex (MSC) has long been proposed to increase protein synthesis efficiency by passing charged tRNAs directly to ribosomes. An alternative is that the MSC repurposes specific synthetases for ex-translational functions that are activated by cues that direct specific enzymes to novel targets. To explore this question, we generated mammalian cell clones in which ArgRS and GlnRS were absent from the MSC to give a stable complex lacking the two enzymes (MSCΔRQ). Protein synthesis, under a variety of stress conditions, was unchanged in MSCΔRQ cells. Most strikingly, levels of charged tRNAGln and tRNAArg remained unchanged and no ribosome pausing was observed at codons for Arg and Gln. Thus, increasing or regulating protein synthesis efficiency is not dependent on ArgRS and GlnRS in the MSC. Alternatively, and consistent with previously reported ex-translational roles, we found manipulations that do not affect protein synthesis but instead MSC cellular localization.
2020-11-18 | GSE158212 | GEO