Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability

Bae, Haneui; Coller, Jeff

doi:10.1016/j.molcel.2022.03.032

Cited by 49 publications

(39 citation statements)

References 76 publications

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“…Within each species, some codons are more frequently used, especially in highly expressed genes, and thought to be “optimal.” Other codons are less widely used and are called “nonoptimal” (Grantham et al, 1980, Ikemura, 1985). Synonymous codon usage is an essential and evolutionarily conserved mechanism of gene regulation: a gene with optimal codons produces dramatically more protein than its nonoptimal counterpart, even when the same primary protein sequence is encoded (dos Reis et al, 2004, Liu et al, 2021, Bae and Coller, 2022). This phenomenon underpins the common practice of codon optimization within heterologous expression systems to increase expression of genes of interest (Ikemura, 1981, Gustafsson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Synonymous codon usage regulates translation initiation

Barrington

Koch

Galindo

et al. 2022

Preprint

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Synonymous codon usage regulates gene expression such that transcripts rich in optimal codons produce significantly more protein than their nonoptimal counterparts. A major unresolved issue has been understanding the mechanisms by which synonymous codons regulate gene expression. We and others have previously shown that nonoptimal codons slow translation elongation speeds and thereby trigger mRNA degradation. However, differences in transcript abundance are not always sufficient to explain differences in protein levels, suggesting there are additional mechanisms by which codon usage regulates gene expression. Using reporter assays in human and Drosophila cells, we found that transcript levels account for less than half of the variation in protein abundance. We demonstrate that the differences at the protein level are not attributable to either protein folding or stability. Instead, we find that mRNAs with nonoptimal codons are bound by fewer ribosomes and that nonoptimal codon usage represses translation initiation. Nonoptimal transcripts are also less bound by the key translation initiation factors eIF4E and eIF4G, providing a mechanistic explanation for their reduced initiation rates. Our results reveal a new mechanism of regulation by codon usage, where nonoptimal codons repress further rounds of translation.

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Section: Introductionmentioning

confidence: 99%

Synonymous codon usage regulates translation initiation

Barrington

Koch

Galindo

et al. 2022

Preprint

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“…Moreover, the model describes how this relationship depends on the overall abundance of the tRNA. Non-optimal codons, for which the abundance of cognate tRNAs is low [2], show a relatively higher TC loading rate increase as ATP increases compared to optimal codons. As a result, the TC loading rate ratio of optimal to nonoptimal codons decreases with ATP concentration (Fig 2F).…”

Section: S4c)mentioning

confidence: 99%

“…Importantly, codons coding for the same amino acid, or synonymous codons, are not functionally equivalent. In particular, codons differ on their optimality for being decoded by the translation machinery, which not only affects the rate of protein production but also the rate of messenger RNA (mRNA) degradation [1], via a pathway termed codon optimality-mediated mRNA degradation [2].…”

Section: Introductionmentioning

confidence: 99%

Cellular energy regulates mRNA translation and degradation in a codon-specific manner

Silva

Zhang

Theodorakis

et al. 2023

Preprint

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Codon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood. Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Biochemical modeling and perturbation data through oxygen deprivation and ATP synthesis inhibition reveal that cellular energy variations non-uniformly affect the decoding kinetics of different codons. This new mechanism of codon effect regulation, independent of tRNA regulation, provides a fundamental mechanistic link between cellular energy metabolism and eukaryotic gene expression.

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“…Certain N-terminal codons in bacterial mRNAs form a weak secondary structure to favor ribosome binding and enhance translation initiation ( Bentele et al, 2013 ; Goodman et al, 2013 ). After initiation, translation elongation is governed by codon optimality, an index of mRNA codon recognition by tRNAs ( Hanson and Coller, 2018 ; Bae and Coller, 2022 ). Codon optimality even impacts mRNA degradation, according to global mRNA sequence and expression correlation analyses ( Hanson and Coller, 2018 ; Carneiro et al, 2019 ; Bae and Coller, 2022 ).…”

Section: Evidence In Support Of the Relative Specificity Hypothesismentioning

confidence: 99%

“…After initiation, translation elongation is governed by codon optimality, an index of mRNA codon recognition by tRNAs ( Hanson and Coller, 2018 ; Bae and Coller, 2022 ). Codon optimality even impacts mRNA degradation, according to global mRNA sequence and expression correlation analyses ( Hanson and Coller, 2018 ; Carneiro et al, 2019 ; Bae and Coller, 2022 ). The ribosome, therefore, by its nature of relative specificity regulates both protein and mRNA expression.…”

Section: Evidence In Support Of the Relative Specificity Hypothesismentioning

confidence: 99%

Relative specificity as an important consideration in the big data era

Zhang

Zeng²

2022

Front. Genet.

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Technological breakthroughs such as high-throughput methods, genomics, single-cell studies, and machine learning have fundamentally transformed research and ushered in the big data era of biology. Nevertheless, current data collections, analyses, and modeling frequently overlook relative specificity, a crucial property of molecular interactions in biochemical systems. Relative specificity describes how, for example, an enzyme reacts with its many substrates at different rates, and how this discriminatory action alone is sufficient to modulate the substrates and downstream events. As a corollary, it is not only important to comprehensively identify an enzyme’s substrates, but also critical to quantitatively determine how the enzyme interacts with the substrates and to evaluate how it shapes subsequent biological outcomes. Genomics and high-throughput techniques have greatly facilitated the studies of relative specificity in the 21st century, and its functional significance has been demonstrated in complex biochemical systems including transcription, translation, protein kinases, RNA-binding proteins, and animal microRNAs (miRNAs), although it remains ignored in most work. Here we analyze recent findings in big data and relative specificity studies and explain how the incorporation of relative specificity concept might enhance our mechanistic understanding of gene functions, biological phenomena, and human diseases.

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Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability

Cited by 49 publications

References 76 publications

Synonymous codon usage regulates translation initiation

Synonymous codon usage regulates translation initiation

Cellular energy regulates mRNA translation and degradation in a codon-specific manner

Relative specificity as an important consideration in the big data era

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