Coding regions affect mRNA stability in human cells

Ashrut Narula,J Matthew Taliaferro,Olivia S Rissland,James Ellis

doi:10.1261/rna.073239.119

Ashrut Narula, J Matthew Taliaferro + Show 2 more

Open Access

https://doi.org/10.1261/rna.073239.119

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Abstract

A new paradigm has emerged that coding regions can regulate mRNA stability in model organisms. Here, due to differences in cognate tRNA abundance, synonymous codons are translated at different speeds, and slow codons then stimulate mRNA decay. To ask if this phenomenon also occurs in humans, we isolated RNA stability effects due to coding regions using the human ORFeome collection. We find that many open reading frame (ORF) characteristics, such as length and secondary structure, fail to provide explanations for how coding regions alter mRNA stability, and, instead, that the ORF relies on translation to impact mRNA stability. Consistent with what has been seen in other organisms, codon use is related to the effects of ORFs on transcript stability. Importantly, we found instability-associated codons have longer A-site dwell times, suggesting for the first time in humans a connection between elongation speed and mRNA decay. Thus, we propose that codon usage alters decoding speeds and so affects human mRNA stability.

Highlights

Transcript destruction is key for controlling gene expression
Given recent reports on the influence of codon use on Messenger RNA (mRNA) stability, we wanted to explore the potential of the open reading frame (ORF) to impact mRNA stability in human cells
Codon use and other ORF features coevolve with mRNA characteristics, all of which have the potential to impact mRNA stability (Schnall-Levin et al 2011; Duan et al 2013; Geisberg et al 2014; Presnyak et al 2015; Neymotin et al 2016)

Summary

Introduction

Transcript destruction is key for controlling gene expression. Messenger RNA (mRNA) decay helps set the overall expression level of genes, but it determines the dynamics of their expression. A major line of research has been to understand both the elements within an RNA that control its stability as well as the mechanisms underlying this regulation. Especially in humans, 3′UTRs contain extensive sequence space that has large regulatory potential while being devoid of other constraints (such as encoding a protein). Regulatory factors, such as RNA binding proteins (RBP), can stably bind the 3′UTR, which is not exposed to the translating ribosome, unlike the 5′UTR or open reading frame (ORF) (Grimson et al 2007). Elements within the 3′UTR, such as those bound by microRNAs (miRNAs), provide our best understanding of the mechanisms and regulation of mRNA decay (Rissland 2016). The decapping enzyme removes the 5′ cap, thereby exposing the body of the transcript to the major cytoplasmic 5′ → 3′ exonuclease, Xrn (Yamashita et al 2005; Chen et al 2009)

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