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Molecular Biology Reports Jan 2022Codon usage bias is the preferential or non-random use of synonymous codons, a ubiquitous phenomenon observed in bacteria, plants and animals. Different species have... (Review)
Review
Codon usage bias is the preferential or non-random use of synonymous codons, a ubiquitous phenomenon observed in bacteria, plants and animals. Different species have consistent and characteristic codon biases. Codon bias varies not only with species, family or group within kingdom, but also between the genes within an organism. Codon usage bias has evolved through mutation, natural selection, and genetic drift in various organisms. Genome composition, GC content, expression level and length of genes, position and context of codons in the genes, recombination rates, mRNA folding, and tRNA abundance and interactions are some factors influencing codon bias. The factors shaping codon bias may also be involved in evolution of the universal genetic code. Codon-usage bias is critical factor determining gene expression and cellular function by influencing diverse processes such as RNA processing, protein translation and protein folding. Codon usage bias reflects the origin, mutation patterns and evolution of the species or genes. Investigations of codon bias patterns in genomes can reveal phylogenetic relationships between organisms, horizontal gene transfers, molecular evolution of genes and identify selective forces that drive their evolution. Most important application of codon bias analysis is in the design of transgenes, to increase gene expression levels through codon optimization, for development of transgenic crops. The review gives an overview of deviations of genetic code, factors influencing codon usage or bias, codon usage bias of nuclear and organellar genes, computational methods to determine codon usage and the significance as well as applications of codon usage analysis in biological research, with emphasis on plants.
Topics: Animals; Anticodon; Base Composition; Biological Evolution; Codon; Codon Usage; Computational Biology; Databases, Genetic; Epistasis, Genetic; Evolution, Molecular; Gene Expression Regulation; Gene Expression Regulation, Plant; Humans; Protein Biosynthesis; RNA, Transfer; Selection, Genetic; Sex Factors; Species Specificity; Structure-Activity Relationship
PubMed: 34822069
DOI: 10.1007/s11033-021-06749-4 -
Molecular Cell Apr 2022Messenger RNA (mRNA) translation by the ribosome represents the final step of a complicated molecular dance from DNA to protein. Although classically considered a... (Review)
Review
Messenger RNA (mRNA) translation by the ribosome represents the final step of a complicated molecular dance from DNA to protein. Although classically considered a decipherer that translates a 64-word genetic code into a proteome of astonishing complexity, the ribosome can also shape the transcriptome by controlling mRNA stability. Recent work has discovered that the ribosome is an arbiter of the general mRNA degradation pathway, wherein the ribosome transit rate serves as a major determinant of transcript half-lives. Specifically, members of the degradation complex sense ribosome translocation rates as a function of ribosome elongation rates. Central to this notion is the concept of codon optimality: although all codons impact translation rates, some are deciphered quickly, whereas others cause ribosome hesitation as a consequence of relative cognate tRNA concentration. These transient pauses induce a unique ribosome conformational state that is probed by the deadenylase complex, thereby inducing an orchestrated set of events that enhance both poly(A) shortening and cap removal. Together, these data imply that the coding region of an mRNA not only encodes for protein content but also impacts protein levels through determining the transcript's fate.
Topics: Codon; Protein Biosynthesis; Proteins; RNA Stability; RNA, Messenger; Ribosomes
PubMed: 35452615
DOI: 10.1016/j.molcel.2022.03.032 -
Oncogene Nov 2021A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis... (Review)
Review
A key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis involves the translation of codons within the mRNA coding sequence into a string of amino acids to form a polypeptide chain. As most amino acids are encoded by multiple codons, the nucleotide sequence of a coding region can vary dramatically without altering the polypeptide sequence of the encoded protein. Although mutations that do not alter the final amino acid sequence are often thought of as silent/synonymous, these can still have dramatic effects on protein output. Because each codon has a distinct translation elongation rate and can differentially impact mRNA stability, each codon has a different degree of 'optimality' for protein synthesis. Recent data demonstrates that the codon preference of a transcriptome matches the abundance of tRNAs within the cell and that this supply and demand between tRNAs and mRNAs varies between different cell types. The largest observed distinction is between mRNAs encoding proteins associated with proliferation or differentiation. Nevertheless, precisely how codon optimality and tRNA expression levels regulate cell fate decisions and their role in malignancy is not fully understood. This review describes the current mechanistic understanding on codon optimality, its role in malignancy and discusses the potential to target codon optimality therapeutically in the context of cancer.
Topics: Codon; Humans; Mutation; Neoplasms; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA, Transfer
PubMed: 34584217
DOI: 10.1038/s41388-021-02022-x -
ELife May 2022Engineering transfer RNAs to read codons consisting of four bases requires changes in tRNA that go beyond the anticodon sequence.
Engineering transfer RNAs to read codons consisting of four bases requires changes in tRNA that go beyond the anticodon sequence.
Topics: Anticodon; Codon; Genetic Code; RNA, Transfer
PubMed: 35543705
DOI: 10.7554/eLife.78869 -
Molecular Cell Jan 2023Nonsense mutations, accounting for >20% of disease-associated mutations, lead to premature translation termination. Replacing uridine with pseudouridine in stop codons...
Nonsense mutations, accounting for >20% of disease-associated mutations, lead to premature translation termination. Replacing uridine with pseudouridine in stop codons suppresses translation termination, which could be harnessed to mediate readthrough of premature termination codons (PTCs). Here, we present RESTART, a programmable RNA base editor, to revert PTC-induced translation termination in mammalian cells. RESTART utilizes an engineered guide snoRNA (gsnoRNA) and the endogenous H/ACA box snoRNP machinery to achieve precise pseudouridylation. We also identified and optimized gsnoRNA scaffolds to increase the editing efficiency. Unexpectedly, we found that a minor isoform of pseudouridine synthase DKC1, lacking a C-terminal nuclear localization signal, greatly improved the PTC-readthrough efficiency. Although RESTART induced restricted off-target pseudouridylation, they did not change the coding information nor the expression level of off-targets. Finally, RESTART enables robust pseudouridylation in primary cells and achieves functional PTC readthrough in disease-relevant contexts. Collectively, RESTART is a promising RNA-editing tool for research and therapeutics.
Topics: Animals; Codon, Nonsense; RNA; Codon, Terminator; Mutation; Protein Biosynthesis; Mammals
PubMed: 36521489
DOI: 10.1016/j.molcel.2022.11.011 -
Nature Genetics Oct 2016Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance...
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs. We also show that dosage compensation may sometimes mask the effects of NMD. Applying the NMD model identifies signatures of both positive and negative selection on NMD-triggering mutations in human tumors and provides a classification for tumor-suppressor genes.
Topics: Animals; Codon, Nonsense; Codon, Terminator; Drosophila; Exons; Genes, Tumor Suppressor; Humans; Models, Genetic; Mutation; Neoplasms; Nonsense Mediated mRNA Decay; Protein Biosynthesis
PubMed: 27618451
DOI: 10.1038/ng.3664 -
Annals of Botany Nov 2017Studies on codon usage in monocots have focused on grasses, and observed patterns of this taxon were generalized to all monocot species. Here, non-grass monocot species... (Review)
Review
BACKGROUND AND AIMS
Studies on codon usage in monocots have focused on grasses, and observed patterns of this taxon were generalized to all monocot species. Here, non-grass monocot species were analysed to investigate the differences between grass and non-grass monocots.
METHODS
First, studies of codon usage in monocots were reviewed. The current information was then extended regarding codon usage, as well as codon-pair context bias, using four completely sequenced non-grass monocot genomes (Musa acuminata, Musa balbisiana, Phoenix dactylifera and Spirodela polyrhiza) for which comparable transcriptome datasets are available. Measurements were taken regarding relative synonymous codon usage, effective number of codons, derived optimal codon and GC content and then the relationships investigated to infer the underlying evolutionary forces.
KEY RESULTS
The research identified optimal codons, rare codons and preferred codon-pair context in the non-grass monocot species studied. In contrast to the bimodal distribution of GC3 (GC content in third codon position) in grasses, non-grass monocots showed a unimodal distribution. Disproportionate use of G and C (and of A and T) in two- and four-codon amino acids detected in the analysis rules out the mutational bias hypothesis as an explanation of genomic variation in GC content. There was found to be a positive relationship between CAI (codon adaptation index; predicts the level of expression of a gene) and GC3. In addition, a strong correlation was observed between coding and genomic GC content and negative correlation of GC3 with gene length, indicating a strong impact of GC-biased gene conversion (gBGC) in shaping codon usage and nucleotide composition in non-grass monocots.
CONCLUSION
Optimal codons in these non-grass monocots show a preference for G/C in the third codon position. These results support the concept that codon usage and nucleotide composition in non-grass monocots are mainly driven by gBGC.
Topics: Araceae; Codon; Genetic Techniques; Genome, Plant; Musa; Phoeniceae; Transcriptome
PubMed: 29155926
DOI: 10.1093/aob/mcx112 -
Cell Reports Dec 2023Nonoptimal synonymous codons repress gene expression, but the underlying mechanisms are poorly understood. We and others have previously shown that nonoptimal codons...
Nonoptimal synonymous codons repress gene expression, but the underlying mechanisms are poorly understood. We and others have previously shown that nonoptimal codons slow translation elongation speeds and thereby trigger messenger RNA (mRNA) degradation. Nevertheless, transcript levels are often insufficient to explain protein levels, suggesting additional mechanisms by which codon usage regulates gene expression. Using reporters in human and Drosophila cells, we find that transcript levels account for less than half of the variation in protein abundance due to codon usage. This discrepancy is explained by translational differences whereby nonoptimal codons repress translation initiation. Nonoptimal transcripts are also less bound by the translation initiation factors eIF4E and eIF4G1, providing a mechanistic explanation for their reduced initiation rates. Importantly, translational repression can occur without mRNA decay and deadenylation, and it does not depend on the known nonoptimality sensor, CNOT3. Our results reveal a potent mechanism of regulation by codon usage where nonoptimal codons repress further rounds of translation.
Topics: Animals; Humans; Codon Usage; Ribosomes; Protein Biosynthesis; Codon; RNA, Messenger; Proteins; Drosophila; Transcription Factors
PubMed: 38096059
DOI: 10.1016/j.celrep.2023.113413 -
Genes & Development Jun 2023In addition to the main, protein-coding, open reading frame (mORF), many eukaryotic mRNAs contain upstream ORFs (uORFs) initiated at AUG or near-cognate codons residing... (Review)
Review
In addition to the main, protein-coding, open reading frame (mORF), many eukaryotic mRNAs contain upstream ORFs (uORFs) initiated at AUG or near-cognate codons residing 5' of the mORF start site. Whereas translation of uORFs generally represses translation of the mORFs, a subset of uORFs serves as a nexus for regulating translation of the mORF. In this review, we summarize the mechanisms by which uORFs can repress or stimulate mRNA translation, highlight uORF-mediated translational repression involving ribosome queuing, and critically evaluate recently described alternatives to the delayed reinitiation model for uORF-mediated regulation of the / mRNAs.
Topics: Codon, Initiator; Protein Biosynthesis; Codon; Ribosomes; RNA, Messenger; Open Reading Frames
PubMed: 37433636
DOI: 10.1101/gad.350752.123 -
Nucleic Acids Research Sep 2016The principles of mRNA decoding are conserved among all extant life forms. We present an integrative view of all the interaction networks between mRNA, tRNA and rRNA:... (Review)
Review
The principles of mRNA decoding are conserved among all extant life forms. We present an integrative view of all the interaction networks between mRNA, tRNA and rRNA: the intrinsic stability of codon-anticodon duplex, the conformation of the anticodon hairpin, the presence of modified nucleotides, the occurrence of non-Watson-Crick pairs in the codon-anticodon helix and the interactions with bases of rRNA at the A-site decoding site. We derive a more information-rich, alternative representation of the genetic code, that is circular with an unsymmetrical distribution of codons leading to a clear segregation between GC-rich 4-codon boxes and AU-rich 2:2-codon and 3:1-codon boxes. All tRNA sequence variations can be visualized, within an internal structural and energy framework, for each organism, and each anticodon of the sense codons. The multiplicity and complexity of nucleotide modifications at positions 34 and 37 of the anticodon loop segregate meaningfully, and correlate well with the necessity to stabilize AU-rich codon-anticodon pairs and to avoid miscoding in split codon boxes. The evolution and expansion of the genetic code is viewed as being originally based on GC content with progressive introduction of A/U together with tRNA modifications. The representation we present should help the engineering of the genetic code to include non-natural amino acids.
Topics: Codon; Genetic Code; Nucleic Acid Conformation; RNA, Transfer; Ribosomes; Thermodynamics
PubMed: 27448410
DOI: 10.1093/nar/gkw608