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Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

ABSTRACT: In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations.

ORGANISM(S): Mus musculus

PROVIDER: GSE56127 | GEO | 2014/07/28

SECONDARY ACCESSION(S): PRJNA242520

REPOSITORIES: GEO

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Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations. Examination of ribosome stalling in cerebella from 4 mouse strains derived from the: C57BL/6J (B6J) strain. The nmf205-/- strain has a homozygous mutation in the gene GTPBP2 while the B6J strain has normal GTPBP2. The n-Tr20 J/J strain has a defect in the n-Tr20 tRNA while the n-Tr20 N/N strain has a functional n-Tr20 tRNA. The 4 strains are the 2x2 combinations of these defects and correctly functioning sequences. 2 replicates for each strain. Please note that only BAM files are included in the records since they form the basis of the study's conclusions. The raw data ribosomal RNA have been filtered and then unique reads mapping to mm10 were computed using tophat and igenome annotations.

2014-07-28 | E-GEOD-56127 | biostudies-arrayexpress

Bump-finder: identification of causal codons to the stalling of ribosomes

Project description:Stalling of the ribosomes on the mRNA has been linked to myriad of molecular and biological functions. While a multitude of algorithms predict codon-usage in ribosome profiling data, no tool exists to predict the context-specific stalling of ribosomes on transcripts. Combining these two features can reveal unprecedented insights in the ribosomal function and their usage across cells and conditions. To overcome this lack of tools to comprehensively analyze these features, we created Bumpfinder, a web-server, that provides comprehensive analytical details on differences in total ribosome occupancy on transcripts, ribosomal occupancy across codons, ribosome-stalling and the underlying causal amino-acids/codons, as well as collisions. Employing Bumpfinder on generated and publicly available ribosome-profiling datasets, we studied the response of various cell types to amino-acid starvation conditions. We observed interesting patterns in response to the biological effects, suggesting the impact of quality control mechanisms of protein synthesis. Complimentary analysis of collided ribosomes demonstrated phased ribosome stalling on the identified sites. Thus, by deciphering context-specific ribosome distribution, Bumpfinder provides unprecedented molecular insights in the ribosome function and mRNA translation during stress response conditions.

2023-12-31 | GSE156443 | GEO

Examination of gene expression in cerebellum of mouse strains B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/-;Gcn2-/-.

Project description:Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of B6J-nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA Arg(UCU) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2Î± (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2alpha kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in B6J-nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress. Examination of gene expression in cerebellum and hippocampus for 4 mice strains derived from C57BL/6J (B6J) strain. Microarray data was performed for 3 week and 5 week old mice in both cerebellum and hippocampus for B6J and B6J-nmf205-/- three replicates each. RNA-Seq data was perform on cerebellum of mice 3 weeks old, three replicates for each genotype: B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/-;Gcn2-/-.

2016-06-15 | E-GEOD-79929 | biostudies-arrayexpress

Examination of gene expression in cerebellum and hippocampus for mouse C57BL/6J WT and nmf205-/-

Project description:Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of B6J-nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA Arg(UCU) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2Î± (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2Î± kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in B6J-nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress. Examination of gene expression in cerebellum and hippocampus for 4 mice strains derived from C57BL/6J (B6J) strain. Microarray data was performed for 3 week and 5 week old mice in both cerebellum and hippocampus for B6J and B6J-nmf205-/- three replicates each. RNA-Seq data was perform on cerebellum of mice 3 weeks old, three replicates for each genotype: B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/-;Gcn2-/-.

2016-06-15 | E-GEOD-79926 | biostudies-arrayexpress

Examination of gene expression in cerebellum of mouse strains B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/-;Gcn2-/-.

Project description:Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of B6J-nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA Arg(UCU) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in B6J-nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.

2016-06-15 | GSE79929 | GEO

Examination of gene expression in cerebellum and hippocampus for mouse C57BL/6J WT and nmf205-/-

Project description:Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of B6J-nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA Arg(UCU) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in B6J-nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.

2016-06-15 | GSE79926 | GEO

Selective stalling of human translation through small molecule engagement of the ribosome nascent chain

Project description:We use ribosome profiling to demonstrate the selectivity of a small molecule, PF-06446846 that inhibits translation of its target by selectively inducing ribosome-stalling in a nascent chain sequence dependent manner.

2017-06-05 | GSE94454 | GEO

Loss of N1-Methylation of G37 in tRNA Induces Ribosome Stalling and Reprograms Gene Expression

Project description:N1-methylation of G37 is required for a subset of tRNAs to maintain the translational reading-frame. While loss of m1G37 increases ribosomal +1 frameshifting, whether it incurs additional translational defects is unknown. Here we address this question by applying ribosome profiling to gain a genome-wide view of the effects of m1G37 deficiency on protein synthesis. Using E. coli as a model, we show that m1G37 deficiency induces ribosome stalling at codons that are normally translated by m1G37-containing tRNAs. Stalling occurs during decoding of affected codons at the ribosomal A site, indicating a distinct mechanism than that of +1 frameshifting, which occurs after the affected codons leave the A site. Enzyme- and cell-based assays show that m1G37 deficiency reduces tRNA aminoacylation and in some cases peptide-bond formation. We observe changes of gene expression in m1G37 deficiency similar to those in the stringent response that is typically induced by deficiency of amino acids. This work demonstrates a previously unrecognized function of m1G37 that emphasizes its role throughout the entire elongation cycle of protein synthesis, providing new insight into its essentiality for bacterial growth and survival.

2021-08-19 | GSE165592 | GEO

Loss of N1-Methylation of G37 in tRNA Induces Ribosome Stalling and Reprograms Gene Expression

Project description:Loss of N1-Methylation of G37 in tRNA Induces Ribosome Stalling and Reprograms Gene Expression

| PRJNA695008 | ENA

DksA Guards Elongating RNA Polymerase Against Ribosome-Stalling-Induced Arrest

Project description:In bacteria, translation-transcription coupling inhibits RNA polymerase (RNAP) stalling. We present evidence suggesting that, upon amino acid starvation, inactive ribosomes promote rather than inhibit RNAP stalling. We developed an algorithm to evaluate genome-wide polymerase progression independently of local noise, and used it to reveal that the transcription factor DksA inhibits promoter-proximal pausing and increases RNAP elongation when uncoupled from translation by depletion of charged tRNAs. DksA has minimal effect on RNAP elongation in vitro and on untranslated RNAs in vivo. In these cases, transcripts can form RNA structures that prevent backtracking. Thus, the effect of DksA on transcript elongation may occur primarily upon ribosome slowing/stalling or at promoter-proximal locations that limit the potential for RNA structure. We propose that inactive ribosomes prevent formation of backtrackblocking mRNA structures and that, in this circumstance, DksA acts as a transcription elongation factor in vivo. Chromatin immunoprecipitation (ChIP) experiments were performed by using antibodies against RNA polymerase b subunit in wild-type and DdksA cells treated with 0.5mg/ml serine hydroxamate (SHX) or untreated. DksA and s70 enrichments were compared to RNAP enrichment by ChIP experiments using antibodies against s70 and DksA in wild-type cells (also in DdksA cells as a negative control for DksA ChIP-chip). Differentially labeled ChIP DNA and genomic DNA were competitively hybridized to an E. coli K-12 MG1655 tiling array with overlapping probes at ~12bp spacing across the entire genome. The series contains 19 datasets.

2014-04-21 | E-GEOD-54669 | biostudies-arrayexpress

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