Codon and amino acid content are associated with mRNA stability in mammalian cells

Abstract

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in the cell and is a major control point for modulating gene expression. In yeast and other model organisms, codon identity is a powerful determinant of transcript stability, contributing broadly to impact half-lives. General principles governing mRNA stability are poorly understood in mammalian systems. Importantly, however, the degradation machinery is highly conserved, thus it seems logical that mammalian transcript half-lives would also be strongly influenced by coding determinants. Herein we characterize the contribution of coding sequence towards mRNA decay in human and Chinese Hamster Ovary cells. In agreement with previous studies, we observed that synonymous codon usage impacts mRNA stability in mammalian cells. Surprisingly, however, we also observe that the amino acid content of a gene is an additional determinant correlating with transcript stability. The impact of codon and amino acid identity on mRNA decay appears to be associated with underlying tRNA and intracellular amino acid concentrations. Accordingly, genes of similar physiological function appear to coordinate their mRNA stabilities in part through codon and amino acid content. Together, these results raise the possibility that intracellular tRNA and amino acid levels interplay to mediate coupling between translational elongation and mRNA degradation rate in mammals.

Formation of HERV-K and HERV-Fc1 Envelope Family Members is Suppressed on Transcriptional and Translational Level

“…Interestingly, codon composition has been shown to directly influence mRNA stability. The impact of codon usage on stability varies between species or cell types [ 44 ] and cannot be predicted certainly today. Moreover, the tRNA pool seems to be dynamic [ 45 ] and not all cells of a given species must behave identically.…”

The Ongoing Quest to Crack the Genetic Code for Protein Production

“…In the past decades, it has been suggested that the translation process may influence mRNA stability in yeast, as reviewed previously (Hanson and Coller, 2018). More recently, this connection gained additional attention in extensive studies in a range of eukaryotes, which all clearly demonstrated a positive correlation between the presence of certain codons in ORFs and the stability of the corresponding mRNAs (Bazzini et al, 2016;Burow et al, 2018;Forrest et al, 2020;Harigaya and Parker, 2016;Hia et al, 2019;Jeacock et al, 2018;Mishima and Tomari, 2016;Narula et al, 2019;de Freitas Nascimento et al, 2018;Presnyak et al, 2015;Wu et al, 2019). In particular, specific codons are observed to be more abundant in mRNAs with a longer halflife.…”

“…On top of codon identity, a link is also suggested between amino acid identity and mRNA decay. A few amino acids are also specifically correlated to more or less stable mRNAs (Bazzini et al, 2016;Forrest et al, 2020;Narula et al, 2019;Wu et al, 2019). It is hypothesized that for these amino acids' higher or lower intracellular concentrations influence the amount of available tRNAs for translating those amino acids and hence influence translation elongation rates and consequently mRNA stability.…”

Conserved codon adaptation in highly expressed genes is associated with higher regularity in mRNA secondary structures

“…Replacing optimal codons in budding yeast by less favorable codons significantly reduces mRNA stability, while reverse substitutions lead to a decreased decay (27). This positive correlation between codon optimality and mRNA stability is well-conserved and has been observed in E. coli (29), Xenopus (30), zebrafish (30), as well as in mammalian cell lines (31). In Saccharomyces cerevisiae (32) the DEAD-box protein Dhh1p is required for the coupling between codon content and mRNA decay (32).…”