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.
Highlights
Messenger RNA stability is a highly regulated process, determining mRNA levels within the expressed transcriptome
We used codon-specific tRNA adaptive indices to define optimal and non-optimal codons, which estimate relative tRNA abundance based on tRNA gene copy number [28,29,44]; importantly, these metrics were highly predictive of differences in codon-specific stability
Given that transcript-level codon stability coefficients (CSC) and amino acid stabilization coefficients (AASCs) values appear to be associated with half-life transcriptome-wide and across these gene groups overall, we further focused on the effects of codon and amino acid content on overall mRNA half-life by considering two gene groups of interest, the cytoplasmic and mitochondrial ribosomal proteins
Summary
Messenger RNA (mRNA) stability is a highly regulated process, determining mRNA levels within the expressed transcriptome. A major mechanism for normal cytoplasmic mRNA degradation is initiated by deadenylation of the 3’-polyA tail. The removal of the polyA tail triggers cleavage of the 5’-7-methylguanosine cap by the DCP1/2 decapping complex, exposing a free 5’-monophosphate group that is recognized by the highly processive 5’-3’ exonuclease XRN1 [2,4,5]. This pathway is most well defined in Saccharomyces cerevisiae, but all of the major factors are conserved from yeast to humans [6,7].
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