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ABSTRACT: Impaired translation fidelity (RNAseq)

PROVIDER: PRJNA1045112 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26948451.fastq.gz	Fastqsanger.gz
	SRR26948452.fastq.gz	Fastqsanger.gz
	SRR26948453.fastq.gz	Fastqsanger.gz
	SRR26948454.fastq.gz	Fastqsanger.gz
	SRR26948455.fastq.gz	Fastqsanger.gz

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Project description:Impaired translation fidelity (RiboSeq)

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Mammalian mitochondrial translation infidelity leads to oxidative stress-induced cell cycle arrest and cardiomyopathy

Project description:Editing of mischarged tRNAs by cytoplasmic aminoacyl-tRNA synthetases (aaRSs) is of high significance for protein homeostasis, whose impairment causes neurodegeneration. However, whether mitochondrial translation needs fidelity and the significance of proofreading (editing) by mitochondrial aaRSs are long-term mysteries. Here, we showed that NIH-3T3 cell line critically depend on the editing of mitochondrial threonyl-tRNA synthetase (Tars2) editing, the disruption of which accumulated Ser-tRNAThr and generated a large abundance of Thr-to-Ser misincorporated peptides. Such infidelity impaired mitochondrial translation and oxidative phosphorylation, causing oxidative stress and cell cycle arrest at G0/G1 phase. ROS removal by N-acetylcysteine relieved abnormal cell proliferation.

2023-08-25 | GSE232410 | GEO

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Project description:The fidelity of translation is crucial in prokaryotes and for the nuclear-encoded proteins of eukaryotes, however little is known about the role of mistranslation in mitochondria and its effects on metabolism. We generated yeast and mouse models with error-prone and hyperaccurate mitochondrial translation fidelity and found that translation rate is more important than translational accuracy for cell function in mammals. We found that mitochondrial mistranslation reduces overall mitochondrial translation and the rate of respiratory complex assembly, however in mammals this is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, mitochondrial stress signaling enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression and cell proliferation, normalizing metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting the mitochondrial stress response. Consequently, the rate of translation cannot be recovered causing dilated cardiomyopathy. Our findings reveal mammalian specific signaling pathways that can respond to changes in the fidelity of mitochondrial protein synthesis

2019-11-08 | PXD015456 | Pride

Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

Project description:Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10-4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum. This study describes the metabolomic analysis of HEK293 cells lines expressing mutant ribosomal protein RPS2 (human A226Y). RPS2 A226Y mutation has been shown to cause misreading and readthrough. Results provide insight into the response to chronic mistranslation in mammalian cells.

2019-09-17 | MTBLS106 | MetaboLights

Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer

Project description:Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis.analysis of transcriptomic changes due to Elp3genetic deletion in cells extracted from PyMT mammary tumors.

2016-09-29 | GSE85810 | GEO

Cancer associated mutants of eIF1A impair Rps3/Rps10 binding and enhance scanning of cell cycle genes [Mars-seq]

Project description:The Ribo-seq analysis demonstrated that eIF1A is predominantly essential for translation of genes with long 5'UTR genes including cell proliferation and cell cycle progression genes. eIF1A depletion causes broad stimulation of initiation in 5’UTRs at near-cognate AUG codons that diminshes the translation initiation fidelity

2018-07-13 | GSE116982 | GEO

Cancer associated mutants of eIF1A impair Rps3/Rps10 binding and enhance scanning of cell cycle genes [Ribo-Seq]

2018-07-13 | GSE116981 | GEO

Bi-directional ribosome scanning controls the stringency of start codon selection

Project description:The fidelity of start codon recognition by ribosomes is paramount during protein synthesis. The textbook knowledge of eukaryotic translation initiation depicts 5’→3’ unidirectional migration of the pre-initiation complex (PIC) along the 5’UTR. In probing translation initiation from ultra-short 5’UTR, we report that an AUG triplet near the 5’ end can be selected via PIC backsliding. The bi-directional ribosome scanning is supported by competitive selection of closely spaced AUG codons and recognition of two initiation sites flanking an internal ribosome entry site. Transcriptome-wide PIC profiling reveals footprints with an oscillation pattern near the 5’ end and start codons. Depleting the RNA helicase eIF4A leads to reduced PIC oscillations and impaired selection of 5’ end start codons. Enhancing the ATPase activity of eIF4A promotes nonlinear PIC scanning and stimulates upstream translation initiation. The helicase-mediated PIC conformational switch may provide an operational mechanism that unifies ribosome recruitment, scanning, and start codon selection.

2021-11-24 | GSE176058 | GEO

RiboSeq and mSeq of two yeast strains

Project description:We report on how the absence of expansion segment 7S from the yeast ribosome alters A-site occupancy along transcripts. This has consequence for local translation rates and protein fidelity.

2024-05-01 | GSE220642 | GEO

Fidelity of translation initiation is required for coordinated respiratory complex assembly

Project description:Fidelity of translation initiation is required for coordinated respiratory complex assembly

| PRJNA542722 | ENA