Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 59-39 decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD.[Keywords: RNA decapping; endonucleolytic RNA cleavage; intron-encoded snoRNA; nonsense-mediated decay; regulation of snoRNA expression; snoRNA host genes] Supplemental material is available for this article.Received June 2, 2014; revised version accepted October 3, 2014.All functional transcripts, whether they are proteincoding (mRNA) or noncoding (ncRNA), are produced as precursor molecules that undergo various processing steps before they take on their final forms. Eukaryotic RNA polymerase II transcribed genes often encode more than one mature RNA species, as exemplified by the alternative splicing of exonic sequences into a variety of transcript isoforms (Braunschweig et al. 2013;Kornblihtt et al. 2013), usage of alternative promoters (Carninci et al. 2006), and the hosting of smaller RNAs, like miRNAs and snoRNAs, within introns (Brown et al. 2008). Regulation of such alternative RNA production confers great plasticity to eukaryotic gene expression because parameters such as expression specificity, stability, localization, and protein-coding potential can be altered between transcript isoforms (McGlincy and Smith 2008;Valen et al. 2009;Kelemen et al. 2013). However, many alternative processing options also increase the likelihood of mistakes, and, throughout the life span of a transcript, its integrity and functionality is continuously being monitored, which ensures that nonfunctional processing byproducts and erroneously processed or outworn molecules are degraded by decay machineries residing in either the nucleus or the cytoplasm (Doma and Parker 2007;Muhlemann and Jensen 2012;Arraiano et al. 2013). For cytoplasmic RNAs with mRNA-like characteristics, the distinction between functional and nonfunctional is carried out by means of translation-dependent...

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