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Charged tRNA profiling of mcf10a, HCC1806 cells, polysome profiling, RNA-Seq and Ribo-Seq in 4T07 cells upon LARS knockdown by shRNA, and RNA-Seq of ribosome-associated RNAs in Lars depleted PyMT tumors

ABSTRACT: In this study, we identify leucyl-tRNA synthetase (LARS) as a breast tumor suppressor. To identify the mechanism underlying LARS-mediated breast tumor suppression, we first conducted charged tRNA profiling to assess charged and total tRNA-Leu expression in cell lines with high and low LARS expression. Expression of select charged and total tRNA-Leu isoacceptors were reduced in cell lines with lower LARS expression. We then conducted RNA-Seq and translation profiling including ribosome profiling (Ribo-Seq), polysome profiling in LARS-depleted cell lines. To test our hypothesis in vivo, we also performed RNA-Seq of ribosome-associated RNAs in Lars depleted PyMT tumors within RiboTag mice. The analyses implicate LARS as a regulator of leucine-rich translation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE176130 | GEO | 2022/01/05

REPOSITORIES: GEO

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Charged tRNA profiling of mcf10a, HCC1806 cells, polysome profiling, RNA-Seq and Ribo-Seq in 4T07 cells upon LARS knockdown by shRNA, and RNA-Seq of ribosome-associated RNAs in Lars depleted PyMT tumors

Project description:Charged tRNA profiling of mcf10a, HCC1806 cells, polysome profiling, RNA-Seq and Ribo-Seq in 4T07 cells upon LARS knockdown by shRNA, and RNA-Seq of ribosome-associated RNAs in Lars depleted PyMT tumors

| PRJNA734953 | ENA

Total tRNA level and tRNA charged fraction in DLD-1 cells treated with 4-hydroxytamoxefen and compared to untreated cells

Project description:Comparison of overall tRNA level and fraction of charged tRNAs upon treatment with 4-hydroxytamoxefen and compared to untreated cells

2019-04-20 | GSE116812 | GEO

tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

Project description:Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks. Using experimental models of senescence escape, we now described that the stability of this suppression relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were upregulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked cell persistence. mTOR inhibition also prevented CIS escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, their corresponding tRNA ligases, YARS and LARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. YARS and LARS inactivation reduced cell emergence and proteomic analysis indicated that this effect was associated with the down-regulation of E2F1 target genes. Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this suppression. !

2021-12-09 | PXD029535 | Pride

METTL6 is a tRNA m3C methyltransferase that regulates translation and cell proliferation

Project description:Here, we identified METTL6 as a bona fide tRNA methyltransferase, catalysing the formation of 3-methylcytidine (m3C) at C32 of specific serine tRNA isoacceptors. Accordingly, deletion of METTL6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as a spontaneous loss of pluripotency

2020-06-18 | GSE144866 | GEO

Ribo-seq of HEK293T overexpressing WT and G240R GARS

Project description:Charcot-Marie-Tooth (CMT) disease can be caused by mutations in Aminoacyl-tRNA-Synthetases, including G240R mutation in Glycyl-tRNA-Synthetase (GARS). Ribo-seq generates snapshots of translating ribosomes on mRNA and therefore allows analysis of ribosome pausing mRNA. Here we performed Ribo-seq on lysates of HEK293T cells overexpressing GARS, WT or G240R, to dissect mechanism of CMT linked with translation. We found that GARS G240R causes pausing of ribosomes with glycine codons in A-site. The effect is specific for 21 nt ribosome-protected fragments, produced by ribosomes with empty A-sites, suggestive of the deficit of charged Glycyl-tRNA in GARS G240R-CMT.

2021-09-14 | E-MTAB-10342 | biostudies-arrayexpress

Modeling ribosome dwell times and relationship with tRNA loading and codon usage in mammals (Ribosome Profiling)

Project description:Protein translation depends on mRNA-specific initiation, elongation, and termination rates. While the regulation of ribosome elongation is well studied in bacteria and yeast, less is known in higher eukaryotes. Here, we combined ribosome and tRNA profiling to investigate the relations between ribosome elongation rates, (aminoacyl-) tRNA levels and codon usage in mammals. We modeled codon-specific ribosome dwell times and translation fluxes from ribosome profiling, considering pair-interactions between ribosome sites. In mouse liver, the model revealed site and codon specific dwell times, as well as codon pair-interactions clustering by amino acids. While translation fluxes varied significantly across diurnal time and feeding regimen, codon dwell times were highly stable, and conserved in human. Fasting had no effect on codon dwell times in mouse liver. Profiling of total and aminoacylated tRNAs revealed highly heterogeneous levels with specific isoacceptor patterns and a correlation with codon usage. tRNAs for isoleucine, asparagine, aspartate and arginine were lowly loaded and conserved in fasted mice. Finally, codons with low levels of charged tRNAs and high codon usage relative to tRNA abundance exhibited long dwell times. Together, these analyses pave the way towards understanding the complex relation between tRNA loading, codon usage and ribosome dwell times in mammals.

2020-03-26 | GSE126383 | GEO

Modeling ribosome dwell times and relationship with tRNA loading and codon usage in mammals (tRNA Profiling)

2020-03-26 | GSE126382 | GEO

Leucyl-tRNA synthetase is a tumor suppressor in breast cancer and enables tumor suppressive translation

Project description:In this study, we identify leucyl-tRNA synthetase (LARS) as a breast tumor suppressor. To identify the mechanism underlying LARS-mediated breast tumor suppression, we conducted TMT-proteomics in PyMT mouse tumors with monoallelic genetic deletion of LARS in the mammary tumor compartment. The analyses implicate LARS as a regulator of leucine-rich protein translation resulting in downregulation of candidate leucine-rich tumor suppressor genes.

2022-01-10 | PXD026609 | Pride

Determination of tRNA aminoacylation levels by high throughput sequencing

Project description:Here we develop a high throughput sequencing method that enables accurate determination of charged tRNA fractions at single base resolution (Charged tRNA-seq). Our method takes advantage of the recently developed DM-tRNA-seq method, but includes additional chemical steps that specifically remove the 3'A residue in the uncharged tRNA. Charging fraction is obtained by counting the fraction of A-ending reads versus A+C-ending reads for each tRNA species. In HEK293T cells, most cytosolic tRNAs are charged at >90% levels, whereas tRNASer and tRNAThr are generally charged at lower levels. These low charging levels were validated using acid denaturing gels. Our method should be widely applicable for investigations of tRNA charging as a parameter for biological regulation.

2017-06-15 | GSE97259 | GEO

McFarland2020 - Synthetase sequestration Model:a combined translation and tRNA charging cycle

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

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