Nonsense mRNA suppression via nonstop decay

Joshua A Arribere,Andrew Z Fire

doi:10.7554/elife.33292

Joshua A Arribere, Andrew Z Fire

Open Access

https://doi.org/10.7554/elife.33292

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Journal: eLife	Publication Date: Jan 8, 2018
Citations: 48	License type: CC BY 4.0

Affiliation: University of California, Santa Cruz, Stanford University

Abstract

Nonsense-mediated mRNA decay is the process by which mRNAs bearing premature stop codons are recognized and cleared from the cell. While considerable information has accumulated regarding recognition of the premature stop codon, less is known about the ensuing mRNA suppression. During the characterization of a second, distinct translational surveillance pathway (nonstop mRNA decay), we trapped intermediates in nonsense mRNA degradation. We present data in support of a model wherein nonsense-mediated decay funnels into the nonstop decay pathway in Caenorhabditis elegans. Specifically, our results point to SKI-exosome decay and pelota-based ribosome removal as key steps facilitating suppression and clearance of prematurely-terminated translation complexes. These results suggest a model in which premature stop codons elicit nucleolytic cleavage, with the nonstop pathway disengaging ribosomes and degrading the resultant RNA fragments to suppress ongoing expression.

Highlights

Nonsense-mediated decay (NMD) is a translational surveillance pathway to mitigate deleterious products of premature stop codons
Our reading suggested that C. elegans has a nonstop mRNA decay pathway, previous efforts were unable to identify molecular players (Parvaz and Anderson, 2007)
Several features have hampered the study of nonstop mRNA decay in vivo

Summary

Introduction

Nonsense-mediated decay (NMD) (reviewed in [He and Jacobson, 2015]) is a translational surveillance pathway to mitigate deleterious products of premature stop codons. In NMD, recognition of an early stop codon destabilizes an mRNA (Morse and Yanofsky, 1969; Baserga and Benz, 1988; Losson and Lacroute, 1979). A large body of literature has highlighted similarities and differences in NMD between yeast and metazoans. While both yeast and metazoan NMD involve a core set of three proteins (UPF1-3 in yeast, SMG-2–4 in metazoans), metazoans require additional proteins for NMD (e.g. SMG-1, –5, and À6). Saccharomyces cerevisiae NMD is thought to occur predominantly through decapping and 5’>3’ exonucleolytic degradation (Muhlrad and Parker, 1994), while studies across metazoans have implicated both exo- and endonucleolytic machineries Saccharomyces cerevisiae NMD is thought to occur predominantly through decapping and 5’>3’ exonucleolytic degradation (Muhlrad and Parker, 1994), while studies across metazoans have implicated both exo- and endonucleolytic machineries (e.g. [Lykke-Andersen, 2002; Lejeune et al, 2003; Gatfield and Izaurralde, 2004; Glavan et al, 2006; Huntzinger et al, 2008; Eberle et al, 2009; Lykke-Andersen et al, 2014; Schmidt et al, 2015; Ottens et al, 2017])

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