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Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors and selection for translation fidelity

ABSTRACT: Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors and selection for translation fidelity

PROVIDER: PRJNA528937 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8782510.fastq.gz	Fastqsanger.gz
	SRR8782502.fastq.gz	Fastqsanger.gz
	SRR8782503.fastq.gz	Fastqsanger.gz
	SRR8782504.fastq.gz	Fastqsanger.gz
	SRR8782505.fastq.gz	Fastqsanger.gz

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Systematic detection of amino acid substitutions in proteomes reveals a mechanistic basis of ribosome errors and selection for translation fidelity

Project description:The translation machinery and the genes it decodes co-evolved to achieve production throughput and accuracy. Nonetheless translation errors are frequent and they affect physiology and protein evolution. Mapping translation errors in proteomes and understanding their causes was hindered by lack of a proteome-wide experimental methodology. We present the first methodology for systematic detection and quantification of errors in entire proteomes. Following proteome mass-spectrometry, we identify in E. coli and yeast peptides whose mass indicates specific amino-acid substitutions. Most substitutions result from codon-anticodon mispairing. Errors occur at sites that evolve rapidly, and that minimally affect energetic stability, indicating selection for high translation fidelity. Ribosome density data show that errors occur at sites where ribosome’s velocity is higher, demonstrating a trade-off between speed and accuracy. Treating bacteria with an aminoglycoside antibiotic or deprivation for specific amino-acids resulted particular patterns of errors. These results reveal a mechanistic and evolutionary basis for translation fidelity.

2019-07-29 | PXD014341 | Pride

Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors and selection for translation fidelity

Project description:The protein translation machinery and the genes it decodes co-evolved to achieve production throughput and accuracy. Nonetheless translation errors are frequent and they affect physiology, fitness and protein evolution. Mapping translation errors in proteomes and understanding their causes was hindered by lack of a proteome-wide experimental methodology. Here, we present the first methodology for systematic detection and quantification of errors in entire proteomes. Following proteome mass-spectrometry, we identify in E. coli and S. cerevisiae peptides whose mass indicates specific amino acid substitutions. Most substitutions occur due to codon-anticodon mispairing within the ribosome. we performed a deep RNA sequencing of the bacterial tRNA pool at the same time points in which we measured the proteome during E. coli culture growth. We compared ratio of abundances between congate and near-cognate tRNAs and found the changes corespond with changes in translation errors.

2019-04-18 | GSE128812 | GEO

High-fidelity base editing mediated by Cpf1-cytidine deaminase fusion

Project description:C-to-T base editing mediated by CRISPR/Cas9 base editors (BEs) needs a G/C-rich PAM and the editing fidelity is compromised by unwanted indels and non-C-to-T substitutions. We developed CRISPR/Cpf1-based BEs to recognize a T-rich PAM and induce efficient C-to-T editing with few indels and/or non-C-to-T substitutions. The requirement of editing fidelity in therapeutic-related trials necessitates the development of CRISPR/Cpf1-based BEs, which also facilitates base editing in A/T-rich regions.

2018-10-16 | GSE105002 | GEO

Fit for Purpose Approach to Evaluate Detection of Amino Acid Substitutions in Shotgun Proteomics

Project description:Raw and processed data in support of manuscript, " Fit for Purpose Approach to Evaluate Detection of Amino Acid Substitutions in Shotgun Proteomics." Taylor J. Lundgren, Patricia L. Clark, Matthew M. Champion

2023-05-24 | MSV000092029 | MassIVE

An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation

Project description:Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type - amino acid (AA) substitutions - despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate the first comprehensive atlas of diverse variant effects for a disease protein, amyloid beta (Aß) that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD variants and many mutations beyond substitutions that accelerate Aß aggregation. Truncations, substitutions, insertions, single- and multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are strongly enriched in the polar N-terminus of Aß. This first comparative atlas for any disease gene highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.

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Adaptation of human cells to protein synthesis errors

Project description:Protein synthesis is a highly regulated process and maintenance of its fidelity is essential to life. Alterations in the components of the protein synthesis machinery, namely RNAs, aminoacyl-tRNA synthetases (aaRS) or tRNA modifying enzymes, increase the level of protein synthesis errors (PSE), and are associated with several conditions, from cancer to neurodegeneration. Still, the cause-effect mechanisms remain to be elucidated in many conditions. In order to have a global picture of how human cells respond and adapt in culture we created stable HEK293 cell lines that express mutant tRNAs. For this, we modified the anticodon of a human serine transfer RNA (tRNASer), to incorporate the amino acid serine (Ser) at various non-cognate sites and overexpressed the wild type tRNASer to evaluate the effects of tRNA misexpression. DNA microarrays were then performed to identify the transcriptional deregulation induced by PSE of cells in culture at different time points (cells passages).

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Project description:Correct charging of tRNAs with their corresponding amino acid is crucial for accurate translation of the genetic code into proteins. However, a growing body of evidence shows that unicellular organisms (bacteria and yeast) can sacrifice translational fidelity to preserve protein synthesis under deprivation of specific essential amino acids.1 Several weeks ago, Pataskar and colleagues described the first instance of codon reassignments caused by amino acid restriction in mammalian cells. Specifically, when human cancer cells were deprived of tryptophan (W), tRNATrp was misacylated with the structurally similar amino acid phenylalanine (F) by tryptophanyl-tRNA synthetase (WARS1), resulting in W>F substitutions in synthesized proteins.2 The authors show that W>F substitutions do preserve translation, but generally result in dysfunctional proteins and that presentation of W>F peptides stimulates T cell-mediated killing. Together this would impair survival of cancer cells that incorporate W>F substitutions in their proteome.2 In the context of growing interest in amino acid depletion diets and related disorders,2 we wondered whether amino acid substitutions are restricted to pathological states like cancer or may represent a more generalized mechanism to maintain translation despite unfavorable circumstances. It is known that ARSs can misactivate tRNAs with structurally similar amino acids3, but editing activity ensures extreme specificity under physiological conditions.4,5 Given the structural similarities between isoleucine and valine, we speculated that isoleucyl-tRNA synthetase (IARS1) would misacylate tRNAIle with valine under isoleucine restriction, leading to I>V substitutions in the proteome. Not only did these substitutions occur in healthy primary human cells, but they also preserved translation and promoted cell viability upon nutritional stress.

2024-11-26 | PXD033426 | Pride

Massively Parallel Reporter Assay of human-specific substitutions in neurodevelopmental enhancers

Project description:We performed a Massively Parallel Reporter Assay (MPRA) to screen >30,000 human-specific substitutions in ChIP-seq-identified Human Gain Enhancers (HGEs) and Human Accelerated Regions (HARs), highly conserved non-coding regions that show accelerated sequence evolution in humans. After comparing human and chimpanzee reference alleles, we used a second MPRA to deconvolute individual substitutions within differentially active enhancers from substitutions in the same fragment and from other variants (human segregating variants or chimpanzee-specific variants) to isolate their specific effects on enhancer activity.

2019-11-26 | GSE140983 | GEO

Mitochondrial DNA allelic substitutions in Parkinson’s disease

Project description:Mitochondrial DNA allelic substitutions in Parkinson’s disease

| PRJNA453701 | ENA

A coding sequence-embedded principle governs translational reading frame fidelity

Project description:Upon initiation at an AUG start codon, the ribosome must maintain the correct reading frame for hundreds of codons in order to produce functional proteins. Although some sequence elements are able to trigger programmed ribosomal frameshifting (PRF), very little is known how the ribosome normally prevents spontaneous frameshift errors. Using high resolution ribosome profiling data sets, we discovered that the translating ribosome uses the 3’ end of 18S rRNA to scan the AUG-like codons after the decoding process. The internal mRNA:rRNA interaction not only contributes to predominant translational pausing, but also provides a post-decoding mechanism to safeguard the ribosome in the correct reading frame. Partially eliminating the AUG-like “sticky” codons in the reporter message leads to increased +1 frameshift errors. Remarkably, mutating the highly conserved CAU triplet of 18S rRNA globally changes codon “stickiness”. Further supporting the role of “sticky” sequences in reading frame maintenance, the codon composition of open reading frames is highly optimized across eukaryotic genomes by minimizing the appearance of AUG-like codons in the frame 2. These results suggest an important layer of information embedded within the protein coding sequences that instructs the ribosome to ensure reading frame fidelity during translation.

2016-04-12 | GSE80156 | GEO

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