Abstract
Nonsense-mediated mRNA decay (NMD) is generally thought to be a eukaryotic mRNA surveillance pathway tasked with the elimination of transcripts harboring an in-frame premature termination codon (PTC). As presently conceived, NMD acting in this manner minimizes the likelihood that potentially toxic polypeptide fragments would accumulate in the cytoplasm. This notion is to be contrasted to the results of systematic RNA-Seq and microarray analyses of NMD substrates in multiple model systems, two different experimental approaches which have shown that many mRNAs identified as NMD substrates fail to contain a PTC. Our recent results provide insight into, as well as a possible solution for, this conundrum. By high-resolution profiling of mRNAs that accumulate in yeast when the principal NMD regulatory genes (UPF1, UPF2, and UPF3) are deleted, we identified approximately 900 NMD substrates, the majority of which are normal-looking mRNAs that lack PTCs. Analyses of ribosomal profiling data revealed that the latter mRNAs tended to manifest elevated rates of out-of-frame translation, a phenomenon that would lead to premature translation termination in alternative reading frames. These results, and related observations of heterogeneity in mRNA isoforms, suggest that NMD should be reconsidered as a probabilistic mRNA quality control pathway that is continually active throughout an mRNA’s life cycle.
Highlights
Nonsense-mediated mRNA decay (NMD) is known as an mRNA surveillance mechanism, but until recently a coherent understanding of the targets of its surveillance activity has been difficult to pin down
The advent of genome-wide microarray and RNA-Seq analyses allowed for the comprehensive assembly of catalogs of NMD substrates in multiple organisms and these studies showed that NMD targets large numbers of apparently normal wild-type mRNAs (He et al 2003; Lelivelt and Culbertson 1999; Rehwinkel et al 2005)
By analyzing ribosomal profiling data for yeast mRNAs that are NMD or non-NMD substrates, we found that the normal-looking yeast NMD substrates have significantly lower ribosome densities throughout their open reading frames than the nonsubstrates, i.e., these mRNAs appear normal they are translated relatively poorly (Celik et al 2017)
Summary
NMD is known as an mRNA surveillance mechanism, but until recently a coherent understanding of the targets of its surveillance activity has been difficult to pin down. This simple functional model was rapidly broadened to a more general role in mRNA quality control with the recognition that the pathway’s substrates included unspliced pre-mRNAs that had entered the cytoplasm (He et al 1993; Pulak and Anderson 1993; Sayani et al 2008), products of alternative splicing (Jaillon et al 2008; Lareau et al 2007; Lykke-Andersen et al 2014; Ni et al 2007), transcripts of pseudogenes or unproductive gene rearrangements (He et al 2003; Li and Wilkinson 1998; McGlincy and Smith 2008), mRNAs subject to programmed frameshifting or leaky scanning (He et al 2003; Welch and Jacobson 1999), and mRNAs with upstream open reading frames (uORFs) (Arribere and Gilbert 2013; Gaba et al 2005; He et al 2003).
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