Abstract
mRNA translation decodes nucleotide into amino acid sequences. However, translation has also been shown to affect mRNA stability depending on codon composition in model organisms, although universality of this mechanism remains unclear. Here, using three independent approaches to measure exogenous and endogenous mRNA decay, we define which codons are associated with stable or unstable mRNAs in human cells. We demonstrate that the regulatory information affecting mRNA stability is encoded in codons and not in nucleotides. Stabilizing codons tend to be associated with higher tRNA levels and higher charged/total tRNA ratios. While mRNAs enriched in destabilizing codons tend to possess shorter poly(A)-tails, the poly(A)-tail is not required for the codon-mediated mRNA stability. This mechanism depends on translation; however, the number of ribosome loads into a mRNA modulates the codon-mediated effects on gene expression. This work provides definitive evidence that translation strongly affects mRNA stability in a codon-dependent manner in human cells.
Highlights
Messenger RNA degradation and mRNA translation represent two fundamental steps in the regulation of gene expression
Human mRNA decay correlates with codon composition in human cell lines To determine whether codon composition affects mRNA stability in human cells, we treated 293T, HeLa and RPE cells with Actinomycin D to block transcription (Figure 1—figure supplement 1A) and measured decay of existing mRNAs by performing time-course mRNA-seq (Figure 1A)
The codon stability coefficient (CSC) scores do not present strong correlation with codon usage (Figure 1—figure supplement 1C). These results imply that codon composition has effects on mRNA stability in humans that are analogous to those found in other species
Summary
Messenger RNA (mRNA) degradation and mRNA translation represent two fundamental steps in the regulation of gene expression. A cell that has been infected by a virus reduces translation Under these conditions, the identity of the codons in the mRNA has less effect on the stability of the mRNA molecule. While less clear in higher organisms, optimal and non-optimal codons tend to be decoded by tRNAs that are highly or poorly expressed, respectively (Bazzini et al, 2016) This suggests that the supply and/or demand for specific tRNAs affects translation elongation, which in turn, affects mRNA stability (Despic and Neugebauer, 2018; Richter and Coller, 2015). Our studies reveal that in human cells, the ribosome interprets two codes within the mRNA: the genetic code, which specifies the amino acid sequence, and a ‘codon-optimality-code’, which shapes mRNA stability
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