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.
The following datasets have been uploaded to NCBI GSE, under the accession number GSE126523.Endogenous mRNA decay:1.293T: 0h, 0h, 1h, 2h,3h,6h,6h2.Hela: 0h,0h,1h,2h,3h,4h,5h,6h,6h3.RPE: 0h,0h,1h,2h,3h,4h,5h,6h,6hORFome:1.293t: 0h, 0h, 1h, 1h, 2h, 2h, 3h, 3h, 4h, 4h, 5h, 5h, 6h, 6h2.K562: 0h, 0h, 1h, 1h, 2h, 2h, 3h, 3h, 4h, 4h, 5h, 5h, 6h, 6hSLAM-seq:1.K562: 0h, 0h, 0h, 2h, 2h, 2h, 4h, 4h, 4h, 6h, 6h, 6h
Three different approaches to measure endogenous and exogenous mRNA decay in four human cell lines (293T, Hela, RPE and K562)NCBI Gene Expression Omnibus,, GSE126523.
HSV1 infection dataNCBI Gene Expression Omnibus, GSE59717.
hydro- tRNA seq, table S1NCBI Gene Expression Omnibus,GSE95683.
TGIRT tRNA seq and charged ratioNCBI Gene Expression Omnibus, GSE97259.
TAIL-seq helaNCBI Gene Expression Omnibus, GSE54114.
PAL-seq 293TNCBI Gene Expression Omnibus, GSE52809.
- Ariel Alejandro Bazzini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the zebrafish were handled according to approved institutional animal care and use committee (IACUC) protocols (#2016-0159) of the Stowers Institute for Medical Research. The protocol was approved on August 18th 2018.
- Nahum Sonenberg, McGill University, Canada
© 2019, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.