scholarly journals Human Retrovirus Codon Usage from tRNA Point of View: Therapeutic Insights

2013 ◽  
Vol 7 ◽  
pp. BBI.S12093 ◽  
Author(s):  
Diego Frias ◽  
Joana P. Monteiro-Cunha ◽  
Aline C. Mota-Miranda ◽  
Vagner S. Fonseca ◽  
Tulio De Oliveira ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Codon Usage ◽  
Supply And Demand ◽  
Mrna Translation ◽  
Protein Translation ◽  
Point Of View ◽  
T Score ◽  
Synonymous Codons ◽  
Trna Species ◽  
Gene Data

The purpose of this study was to investigate the balance between transfer ribonucleic acid (tRNA) supply and demand in retrovirus-infected cells, seeking the best targets for antiretroviral therapy based on the hypothetical tRNA Inhibition Therapy (TRIT). Codon usage and tRNA gene data were retrieved from public databases. Based on logistic principles, a therapeutic score (T-score) was calculated for all sense codons, in each retrovirus-host system. Codons that are critical for viral protein translation, but not as critical for the host, have the highest T-score values. Theoretically, inactivating the cognate tRNA species should imply a severe reduction of the elongation rate during viral mRNA translation. We developed a method to predict tRNA species critical for retroviral protein synthesis. Four of the best TRIT targets in HIV-1 and HIV-2 encode Large Hydrophobic Residues (LHR), which have a central role in protein folding. One of them, codon CUA, is also a TRIT target in both HTLV-1 and HTLV-2. Therefore, a drug designed for inactivating or reducing the cytoplasmatic concentration of tRNA species with anticodon TAG could attenuate significantly both HIV and HTLV protein synthesis rates. Inversely, replacing codons ending in UA by synonymous codons should increase the expression, which is relevant for DNA vaccine design.

scholarly journals Bacterial Ribonuclease MazF-Mediated Apoptosis as Potential Cancer Therapy

2021 ◽  
Author(s):  
Maryam Saffarian Abbas Zadeh ◽  
Rebecca Anne MacPherson ◽  
Guohui Huang ◽  
Hui Ding ◽  
Rhonda Reigers Powell ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Cell Lines ◽  
Mrna Translation ◽  
Protein Translation ◽  
Programmed Death ◽  
Inhibition Of Protein Synthesis ◽  
Cancer Agent ◽  
Cell Suicide ◽  
The Impact

Abstract Programmed cell death is a dynamic and critical mechanism of cell suicide in eukaryotes and prokaryotes. MazF is a ribonuclease protein involved in bacterial intracellular programmed death. This protein cleaves mRNAs at ACA sequences, leading to inhibition of protein synthesis and triggering cell death. Given that cancer is heterogenic and has varied susceptibility to treatment, we examined the impact of MazF proteins on the growth and viability of three cancer cell lines: MCF7, HT29, and AGS. These cell lines were transfected with ACA-less mazF mRNAs and evaluated for MazF-mediated cell death. The data illustrated that efficient MazF translation leads to a significant reduction in cell viability and is modulated by structural elements of ACA-less mazF mRNAs. In the presence of MazF, the levels of activated caspase-3 and -7 were significantly elevated in transfected cells, confirming the occurrence of apoptosis. We also quantified mRNA translation on a single-cell basis in MCF7 and AGS cell lines to examine MazF-mediated inhibition of protein synthesis. MazF expression significant decreases the levels of protein translation in the examined cell lines. This is the first report of MazF as a potential anti-cancer agent via induction of apoptosis in MCF7, AGS, and HT-29 cell lines.

scholarly journals Analysis of computational codon usage models and their association with translationally slow codons

2020 ◽  
Author(s):  
Gabriel Wright ◽  
Anabel Rodriguez ◽  
Jun Li ◽  
Patricia L. Clark ◽  
Tijana Milenković ◽  
...  
Keyword(s):  
Codon Usage ◽  
Computational Models ◽  
Selective Pressure ◽  
Synonymous Codon ◽  
Ground Truth ◽  
Protein Translation ◽  
Weak Correlation ◽  
Experimental Conditions ◽  
Synonymous Codons ◽  
Genome Wide

AbstractImproved computational modeling of protein translation rates, including better prediction of where translational slowdowns along an mRNA sequence may occur, is critical for understanding co-translational folding. Because codons within a synonymous codon group are translated at different rates, many computational translation models rely on analyzing synonymous codons. Some models rely on genome-wide codon usage bias (CUB), believing that globally rare and common codons are the most informative of slow and fast translation, respectively. Others use the CUB observed only in highly expressed genes, which should be under selective pressure to be translated efficiently (and whose CUB may therefore be more indicative of translation rates). No prior work has analyzed these models for their ability to predict translational slowdowns. Here, we evaluate five models for their association with slowly translated positions as denoted by two independent ribosome footprint (RFP) count experiments from S. cerevisiae, because RFP data is often considered as a “ground truth” for translation rates across mRNA sequences. We show that all five considered models strongly associate with the RFP data and therefore have potential for estimating translational slowdowns. However, we also show that there is a weak correlation between RFP counts for the same genes originating from independent experiments, even when their experimental conditions are similar. This raises concerns about the efficacy of using current RFP experimental data for estimating translation rates and highlights a potential advantage of using computational models to understand translation rates instead.

scholarly journals Codon usage of highly expressed genes affects proteome-wide translation efficiency

2018 ◽  
Vol 115 (21) ◽  
pp. E4940-E4949 ◽  
Author(s):  
Idan Frumkin ◽  
Marc J. Lajoie ◽  
Christopher J. Gregg ◽  
Gil Hornung ◽  
George M. Church ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Protein Translation ◽  
Translation Efficiency ◽  
Synonymous Codons ◽  
Codon Composition ◽  
Theoretical Predictions ◽  
Highly Expressed Genes

Although the genetic code is redundant, synonymous codons for the same amino acid are not used with equal frequencies in genomes, a phenomenon termed “codon usage bias.” Previous studies have demonstrated that synonymous changes in a coding sequence can exert significantciseffects on the gene’s expression level. However, whether the codon composition of a gene can also affect the translation efficiency of other genes has not been thoroughly explored. To study how codon usage bias influences the cellular economy of translation, we massively converted abundant codons to their rare synonymous counterpart in several highly expressed genes inEscherichia coli. This perturbation reduces both the cellular fitness and the translation efficiency of genes that have high initiation rates and are naturally enriched with the manipulated codon, in agreement with theoretical predictions. Interestingly, we could alleviate the observed phenotypes by increasing the supply of the tRNA for the highly demanded codon, thus demonstrating that the codon usage of highly expressed genes was selected in evolution to maintain the efficiency of global protein translation.

Are synonymous codons indeed synonymous?

2012 ◽  
Vol 3 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Pál Venetianer
Keyword(s):  
Protein Synthesis ◽  
Synonymous Codon ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Two Factors ◽  
Trna Species ◽  
Frequency Of Occurence

AbstractIt has long been known that the distribution and frequency of occurence of synonymous codons can vary greatly among different species, and that the abundance of isoaccepting tRNA species could also be very different. The interaction of these two factors may influence the rate and efficiency of protein synthesis and therefore synonymous mutations might influence the fitness of the organism and cannot be treated generally as ‘neutral’ in an evolutionary sense. These general effects of synonymous mutations, and their possible role in evolution, have been discussed in several recent papers. This review, however, will only deal with the influence of synonymous codon replacements on the expression of individual genes. It will describe the possible mechanisms of such effects and will present examples demonstrating the existence and effects of each of these mechanisms.

scholarly journals Community control in cellular protein production: consequences for amino acid starvation

2015 ◽  
Vol 373 (2056) ◽  
pp. 20150107 ◽  
Author(s):  
Frank S. Heldt ◽  
Chris A. Brackley ◽  
Celso Grebogi ◽  
Marco Thiel
Keyword(s):  
Amino Acid ◽  
Protein Production ◽  
Control Mechanism ◽  
Supply And Demand ◽  
Mrna Translation ◽  
Cellular Protein ◽  
Amino Acid Starvation ◽  
Community Control ◽  
Trna Species ◽  
A Cell

Deprivation of essential nutrients can have stark consequences for many processes in a cell. We consider amino acid starvation, which can result in bottlenecks in mRNA translation when ribosomes stall due to lack of resources, i.e. tRNAs charged with the missing amino acid. Recent experiments also show less obvious effects such as increased charging of other (non-starved) tRNA species and selective charging of isoaccepting tRNAs. We present a mechanism which accounts for these observations and shows that production of some proteins can actually increase under starvation. One might assume that such responses could only be a result of sophisticated control pathways, but here we show that these effects can occur naturally due to changes in the supply and demand for different resources, and that control can be accomplished through selective use of rare codons. We develop a model for translation which includes the dynamics of the charging and use of aminoacylated tRNAs, explicitly taking into account the effect of specific codon sequences. This constitutes a new control mechanism in gene regulation which emerges at the community level, i.e. via resources used by all ribosomes.

scholarly journals Cortical wiring by synapse-specific control of local protein synthesis

2021 ◽  
Author(s):  
Clémence Bernard ◽  
David Exposito-Alonso ◽  
Martijn Selten ◽  
Stella Sanalidou ◽  
Alicia Hanusz-Godoy ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Synapse Formation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Synaptic Proteins ◽  
Local Synthesis ◽  
Local Protein Synthesis ◽  
Mouse Cerebral Cortex ◽  
A Cell ◽  
Local Protein

Neurons use local protein synthesis as a mechanism to support their morphological complexity, which requires independent control across multiple subcellular compartments including individual synapses. However, to what extent local translation is differentially regulated at the level of specific synaptic connections remains largely unknown. Here, we identify a signaling pathway that regulates the local synthesis of proteins required for the formation of excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves the regulation of the mTORC1 inhibitor Tsc2 by the receptor tyrosine kinase ErbB4, which enables the local control of mRNA translation in a cell type-specific and synapse-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins that regulates the formation of excitatory inputs on PV+ interneurons downstream of ErbB4 signaling. Our work demonstrates that local protein translation is regulated at the level of specific connections to control synapse formation in the nervous system.

scholarly journals Protein synthesis regulation by leucine

2010 ◽  
Vol 46 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Daiana Vianna ◽  
Gabriela Fullin Resende Teodoro ◽  
Francisco Leonardo Torres-Leal ◽  
Julio Tirapegui
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Mrna Translation ◽  
Protein Translation ◽  
Cellular Effects ◽  
Cellular Processes ◽  
High Protein Diets

In vivo and in vitro studies have demonstrated that high protein diets affect both protein synthesis and regulation of several cellular processes. The role of amino acids as substrate for protein synthesis has been established in the literature. However, the mechanism by which these amino acids modulate transcription and regulate the mRNA translation via mTOR-dependent signaling pathway has yet to be fully determined. It has been verified that mTOR is a protein responsible for activating a cascade of biochemical intracellular events which result in the activation of the protein translation process. Of the aminoacids, leucine is the most effective in stimulating protein synthesis and reducing proteolysis. Therefore, it promotes a positive nitrogen balance, possibly by favoring the activation of this protein. This amino acid also directly and indirectly stimulates the synthesis and secretion of insulin, enhancing its anabolic cellular effects. Therefore, this review aimed to identify the role of leucine in protein synthesis modulation and to discuss the metabolic aspects related to this aminoacid.

Maximizing Transcription Efficiency Causes Codon Usage Bias

Genetics ◽  
1996 ◽  
Vol 144 (3) ◽  
pp. 1309-1320 ◽  
Author(s):  
Xuhua Xia
Keyword(s):  
Protein Synthesis ◽  
Metabolic Rate ◽  
Codon Usage ◽  
High Metabolic Rate ◽  
Initiation Rate ◽  
Synonymous Codons ◽  
Mrna Concentration ◽  
Initiation Of Translation ◽  
Transcription Efficiency ◽  
Transcriptional Process

Abstract The rate of protein synthesis depends on both the rate of initiation of translation and the rate of elongation of the peptide chain. The rate of initiation depends on the encountering rate between ribosomes and mRNA; this rate in turn depends on the concentration of ribosomes and mRNA. Thus, patterns of codon usage that increase transcriptional efficiency should increase mRNA concentration, which in turn would increase the initiation rate and the rate of protein synthesis. An optimality model of the transcriptional process is presented with the prediction that the most frequently used ribonuclectide at the third codon sites in mRNA molecules should be the same as the most abundant ribonucleotide in the cellular matrix where mRNA is transcribed. This prediction is supported by four kinds of evidence. First, A-ending codons are the most frequently used synonymous codons in mitochondria, where ATP is much more abundant than that of the three other ribonucleotides. Second, A-ending codons are more frequently used in mitochondrial genes than in nuclear genes. Third, protein genes from organisms with a high metabolic rate use more A-ending codons and have higher A content in their introns than those from organisms with a low metabolic rate.

Focusing on mRNA Granules and Stalled Polysomes Amidst Diverse Mechanisms Underlying mRNA Transport, mRNA Storage, and Local Translation

2020 ◽  
Author(s):  
Mina N. Anadolu ◽  
Wayne S. Sossin
Keyword(s):  
Protein Synthesis ◽  
Liquid Phase ◽  
Mrna Translation ◽  
Rna Transport ◽  
P Bodies ◽  
Rna Granules ◽  
Mrna Granules ◽  
Transport Particle ◽  
As Stress ◽  
The Individual

In neurons, mRNAs are transported to distal sites to allow for localized protein synthesis. There are many diverse mechanisms underlying this transport. For example, an individual mRNA can be transported in an RNA transport particle that is tailored to the individual mRNA and its associated binding proteins. In contrast, some mRNAs are transported in liquid-liquid phase separated structures called neuronal RNA granules that are made up of multiple stalled polysomes, allowing for rapid initiation-independent production of proteins required for synaptic plasticity. Moreover, neurons have additional types of liquid-liquid phase–separated structures containing mRNA, such as stress granules and P bodies. This chapter discusses the relationships between all of these structures, what proteins distinguish them, and the possible roles they play in the complex control of mRNA translation at distal sites that allow neurons to use protein synthesis to refine their local proteome in many different ways.

scholarly journals Upregulation of 5′-terminal oligopyrimidine mRNA translation upon loss of the ARF tumor suppressor

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyle A. Cottrell ◽  
Ryan C. Chiou ◽  
Jason D. Weber
Keyword(s):  
Protein Synthesis ◽  
Tumor Cells ◽  
Ribosomal Proteins ◽  
Human Cancer ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Translational Efficiency ◽  
Gene Encoding ◽  
Terminal Oligopyrimidine ◽  
Ribosome Export

AbstractTumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As such, tumor cells must acquire enhanced ribosome production. How the numerous mutations in tumor cells ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we show that ARF is a major suppressor of 5′-terminal oligopyrimidine mRNA translation. Genes with increased translational efficiency following loss of ARF include many ribosomal proteins and translation factors. Knockout of p53 largely phenocopies ARF loss, with increased protein synthesis and expression of 5′-TOP encoded proteins. The 5′-TOP regulators eIF4G1 and LARP1 are upregulated in Arf- and p53-null cells.

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