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Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation (RNA-seq)

ABSTRACT: The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE223662 | GEO | 2023/03/05

REPOSITORIES: GEO

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Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation [ATAC-seq]

Project description:The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

2023-03-05 | GSE200783 | GEO

Copy number variation in tRNA isodecoders impairs mammalian development and balanced translation

Project description:The number of tRNA isodecoder genes has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-seq, RNA-seq and proteomics we observed distinct molecular consequences of individual tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoders compensate for the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least four tRNA-Phe isodecoders is required for embryonic development and survival. The loss of tRNA-Phe-1-1 and any other three tRNA-Phe genes causes embryonic lethality indicating that tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA isodecoder genes is required to buffer translation and viability in mammals.

2023-04-19 | PXD029684 | Pride

Mistranslation and developmental defects in an allelic series of tRNA isodecoder deletions [Ribo-seq]

Project description:Mistranslation and developmental defects in an allelic series of tRNA isodecoder deletions [Ribo-seq]

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Transcriptome profile of S. cerevisiae strains expressing mistranslating tRNAs

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 assess the transcriptome changes in yeast cells expressing two different mistranslating tRNA variants which mistranslate at similar frequencies (of ~ 3%) but result in different substitutions, namely alanine at proline codons or serine at arginine codons.

2021-05-11 | GSE174145 | GEO

Transcription profiling of yeast in response to mRNA mistranslation after 20 hours of induction

Project description:Transcriptome analysis in cells after 20 hours of mistranslation induction in relation to control cells at the same time point where mistranslation was not induced (without the inducible tRNA construction)

2010-10-01 | E-MTAB-165 | biostudies-arrayexpress

Identification of proline to serine mistranslation in Drosophila melanogaster pupae

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

Identification of tRNA sequences in Lactococcus lactis

Project description:we report the identification and sequences of the tRNAome of industrially relevant microorganism Lactococcus lactis Three Next Generation sequencing runs annotated as S1, S2 and S3 were performed. Cells were harvested at exponential phase and tRNA was isolated. S1 and S2 were spiked with Phe-tRNAGAA from yeast and Lys-tRNAUUU from E. coli prior to cell lysis. S3 was spiked with Phe-tRNAGAA from yeast and Lys-tRNAUUU from E. coli before the library preparation to estimate the possible loss of tRNA in the extraction process.

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Evolution of robustness to protein mistranslation by accelerated protein turnover

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

Evolution of robustness to protein mistranslation by accelerated protein turnover

2015-11-06 | GSE65718 | GEO

Identifying the transcriptomic effects of tRNA-induced proline-to-serine mistranslation in Drosophila melanogaster

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

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