Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway

Abstract

The nonsense-mediated mRNA decay (NMD) pathway is a specialized mRNA degradation pathway that degrades select mRNAs. This pathway is conserved in all eukaryotes examined so far, and it triggers the degradation of mRNAs that prematurely terminate translation. Originally identified as a pathway that degrades mRNAs with premature termination codons as a result of errors during transcription, splicing, or damage to the mRNA, NMD is now also recognized as a pathway that degrades some natural mRNAs. The degradation of natural mRNAs by NMD has been identified in multiple eukaryotes, including Saccharomyces cerevisiae, Drosophila melanogaster, Arabidopsis thaliana, and humans. S. cerevisiae is used extensively as a model to study natural mRNA regulation by NMD. Inactivation of the NMD pathway in S. cerevisiae affects approximately 10% of the transcriptome. Similar percentages of natural mRNAs in the D. melanogaster and human transcriptomes are also sensitive to the pathway, indicating that NMD is important for the regulation of gene expression in multiple organisms. NMD can either directly or indirectly regulate the decay rate of natural mRNAs. Direct NMD targets possess NMD-inducing features. This minireview focuses on the regulation of natural mRNAs by the NMD pathway, as well as the features demonstrated to target these mRNAs for decay by the pathway in S. cerevisiae. We also compare NMD-targeting features identified in S. cerevisiae with known NMDtargeting features in other eukaryotic organisms.

Unique Aspects of Plant Nonsense-Mediated mRNA Decay

“…NMD uses a set of factors to sense the integrity of translation termination and eliminate transcripts with PTCs or features that lead to the recognition of TCs as premature (reviewed in [4][5][6][7][8]). The NMD factors UPF1, UPF2, and UPF3 are conserved in all eukaryotes.…”

“…The EDS1-PAD4 complex is essential (4) for salicylic acid (SA) synthesis from chorismate, which is catalyzed by iso-chorismatesynthase 1 (ICS1) (5). In a positive feedback loop (6), SA enhances the transcription of EDS1 and PAD4. SA also enhances the transcription of Nonexpressor-of-PR-genes-1 (NPR1) (7).…”

“…NMD is one of several quality-control mechanisms that couple aberrant translation elongation or termination to accelerated RNA decay (reviewed in [1-3]). NMD eliminates aberrant transcripts that contain premature termination codons (PTCs), thereby preventing the accumulation of truncated, potentially deleterious proteins (reviewed in [4][5][6][7][8][9]). The NMD process has a profound impact on the plant transcriptome [10][11][12].…”

mRNAs involved in copper homeostasis are regulated by the nonsense-mediated mRNA decay pathway depending on environmental conditions

“…Previous studies in S. cerevisiae have identified features that target natural mRNAs to the pathway. These features include mRNAs subject to leaky ribosomal scanning (Welch and Jacobson, 1999), a translated upstream open reading frame (uORF) (Gaba et al, 2005), À1 ribosomal frameshifts (into an alternative reading frame) (Belew et al, 2011(Belew et al, , 2014, inefficiently spliced pre-mRNAs (He et al, 1993), and mRNAs with atypically long 3 0 -untranslated regions (UTRs) (Deliz-Aguirre et al, 2011;Kebaara and Atkin, 2009;Parker, 2012;Peccarelli and Kebaara, 2014b;Rebbapragada and Lykke-Andersen, 2009;Schweingruber et al, 2013). One specific targeting mechanism of interest is the presence of a long 3 0 -UTR on an mRNA (Deliz-Aguirre et al, 2011;Kebaara and Atkin, 2009;Rebbapragada and Lykke-Andersen, 2009).…”

Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites

“…These unspliced transcripts might be insensitive to NMD due to the lack of a downstream exon junction complex since only one intron is present in the gene. On the other hand, we cannot exclude that NMD may be activated by the long 3′-UTR left by PTCs in LDH and ENO immature transcripts, as observed in yeast in a model known as the faux untranslated region model (Peccarelli and Kebaara 2014). The faux untranslated region model posits that NMD occurs because the Pab1p or another factor bound to the poly(A) tail are not in close proximity to the terminating ribosome to enable interaction of Pab1p with release factor 3 (eRF3p), which is bound to the terminating ribosome and thus establishes the correct mRNP context for a normal translation termination event.…”