Serine mistranslation induces the integrated stress response through the P1 stalk
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1200745 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31782593_1.fastq.gz | Fastqsanger.gz | |||
| SRR31782593_2.fastq.gz | Fastqsanger.gz | |||
| SRR31782594_1.fastq.gz | Fastqsanger.gz | |||
| SRR31782594_2.fastq.gz | Fastqsanger.gz | |||
| SRR31782595_1.fastq.gz | Fastqsanger.gz |
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Project description:Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that support robust and accurate protein synthesis. A rapidly expanding number of studies show that mutations in aaRSs lead to multiple human diseases, including neurological disorders and cancer. Much remains unknown about how aaRS mutations impact human health. In particular, how aminoacylation errors affect stress responses and fitness in eukaryotic cells remains poorly understood. The integrated stress response (ISR) is an adaptive mechanism in response to multiple stresses. However, chronic activation of the ISR contributes to the development of multiple diseases (e.g., neuropathies). Here we show that Ser misincorporation into Ala and Thr codons, resulting from aaRS editing defects or mutations in tRNAs, constitutively active the ISR. Such activation does not appear to depend on the accumulation of uncharged tRNAs, implicating that Ser mistranslation may lead to ribosome stalling and collision.
2024-12-23 | GSE284986 | GEO
Project description:Mistranslation describes the misincorporation of an amino acid into a nascent polypeptide. Mistranslation has diverse effects on multicellular eukaryotes and is implicated in several human diseases. We introduced a mistranslating serine transfer RNA (tRNA) into Drosophila melanogaster that misincorporates serine at proline codons and found that it affected male and female flies differently. Here, we compare the transcriptomic response of male and female flies to mistranslation to identify cellular pathways that underlie this sex-specific response. Both males and females downregulated genes associated with metabolism in response to proline-to-serine mistranslation. Only males downregulated genes associated with developmental processes and response to negative stimuli such as infection, whereas only females downregulated aerobic respiration and ATP synthesis genes. Both sexes upregulated genes associated with gametogenesis but females upregulated cell cycle and DNA maintenance genes, suggesting that mistranslation may compromise genome integrity in females. This transcriptomic analysis advances our understanding of how males and females respond to mistranslation and has important implications for future studies that examine the influence of mistranslation on disease.
2024-05-11 | GSE256332 | GEO
Project description:To investigate how organisms mitigate the deleterious effects of mistranslation during evolution, a mutant tRNA was expressed in S. cerevisiae. The expression of Candida Ser-tRNACAG from a low copy plasmid in S. cerevisiae promoted mistranslation events by random incorporation of both serine and leucine at CUG codons. As mistranslation causes an overload of the protein quality pathways, it disrupts cellular protein homeostasis leading to a major fall in fitness. Laboratory evolutionary experiments were performed to study whether the fitness cost of mistranslation can be lowered. We also wanted to identify the cost-reduction strategy: reducing the frequencies of errors (mitigation), or increasing tolerance to errors (robustness), either by global or local activities.
2015-11-06 | GSE65718 | GEO
Project description:Transfer RNAs (tRNAs) are the adaptor molecules required for reading of the genetic code and the accurate production of proteins. tRNA variants can lead to genome-wide mistranslation, the misincorporation of amino acids not specified by the standard genetic code, into nascent proteins. While genome sequencing has identified putative mistranslating tRNA variants in human populations, little is known regarding how mistranslation affects multicellular organisms. Here, we create a Drosophila melanogaster model for mistranslation by integrating a serine tRNA variant that mistranslates serine for proline (tRNA(Ser)[UGG, G26A]) into the fly genome. Using mass spectrometry, we find that tRNA(Ser)[UGG, G26A] misincorporates serine for proline at a frequency of ~ 0.6% per codon. This model will enable studies into the synergistic effects of mistranslating tRNA variants and disease-causing alleles.
2021-09-18 | PXD028498 | Pride
Project description:Mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all cells. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. The goal of this study was to detect and quantify mistranslation from a serine tRNA variant with proline UGG anticodon and G26A secondary mutation engineered in yeast
2022-08-12 | PXD032063 | Pride
Project description:HLA Class I antigen processing and presentation (APP) is a highly regulated process that enables CD8+ T cell immunosurveillance. APP begins with the ribosomal synthesis of a source antigen, yet the role of ribosomes, particularly specialized ribosomes, in antigen presentation is poorly understood. Here, we show that the presence of the “P-stalk” on the ribosome enhances antigen presentation. The addition of the P-stalk to the ribosome is stimulated by cytokines that upregulate APP components, and knockdown of one of the P-stalk proteins (P1) reduces T cell recognition of tumor cells. Mechanistically, we show that P1-containing ribosomes exhibit enhanced translation of HLA Class I molecules and accessory APP components. Finally, analysis of patient data reveals that the mRNA expression of the P-stalk proteins positively correlates with CD8+ T cell infiltration, a trend not seen for other ribosomal proteins. In all, we demonstrate that the presence of the P-stalk defines a specialized ribosome population that enhances antigen presentation, something that may be exploited by cancer cells to escape immunosurveillance.
2024-10-23 | GSE230060 | GEO
Project description:To investigate how organisms mitigate the deleterious effects of mistranslation during evolution, a mutant tRNA was expressed in S. cerevisiae. The expression of Candida Ser-tRNACAG from a low copy plasmid in S. cerevisiae promoted mistranslation events by random incorporation of both serine and leucine at CUG codons. As mistranslation causes an overload of the protein quality pathways, it disrupts cellular protein homeostasis leading to a major fall in fitness. Laboratory evolutionary experiments were performed to study whether the fitness cost of mistranslation can be lowered. We also wanted to identify the cost-reduction strategy: reducing the frequencies of errors (mitigation), or increasing tolerance to errors (robustness), either by global or local activities. Gene expression was measured in the ancestor (non-evolved) lineage in two different situations: 1) carrying an empty vector and 2) expressing the mutant Ser-tRNACAG. Gene expression was also measured in three ambiguously evolved lineages (B3, D11, H9) in both situations (carrying an empty vector and expressing the mutant tRNA). Three independent experiments were performed for each lineage. Non-evolved strain with empty vector was used as control sample.
2015-11-06 | E-GEOD-65718 | biostudies-arrayexpress
Project description:The leucine CUG codon was reassigned to serine in the fungal pathogen Candida albicans. To clarify the biological role of this tuneable codon ambiguity on drug resistance, we evolved C. albicans strains that were engineered to mistranslate the CUG codon at constitutively elevated levels, in the presence and absence of the antifungal drug fluconazole. Elevated levels of mistranslation resulted in the rapid acquisition of resistance to fluconazole.
2016-10-27 | E-SYBR-13 | biostudies-arrayexpress
Project description:Identifying the transcriptomic effects of tRNA-induced proline-to-serine mistranslation in Drosophila melanogaster
| PRJNA1079207 | ENA
Project description:Mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all cells. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. The goal of this study was to detect mistranslation from two different tRNA variants. The first variant, tRNA-Pro-G3:U70, has a mutation in its acceptor stem creating a G3:U70 base pair which is the key identity element for the alanine tRNA synthetase. This tRNA should be charged with alanine and mis-incorporate alanine at proline codons. The second variant, tRNA-Ser-UCU,G26A, is a serine tRNA with an arginine anticodon and a G26A secondary mutation to dampen function and prevent lethal levels of mistranslation. This tRNA should mis-incorporate serine at arginine codons.
2021-05-17 | PXD025934 | Pride