Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes.
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 5'-3' 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.
Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark;
Søren
S
Lykke-Andersen
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
Yun
Y
Chen
Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark;
Britt R
BR
Ardal
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
Berit
B
Lilje
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
Johannes
J
Waage
The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
Albin
A
Sandelin
Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark;
Torben Heick
TH
Jensen
D004720:Endonucleases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms; D012326:RNA Splicing; D020537:RNA, Small Nucleolar / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases
D004720:Endonucleases; D020033:Protein Isoforms; D020537:RNA, Small Nucleolar; D019098:Telomerase; C512261:SMG6 protein, human; D004722:Endoribonucleases
RNA decapping; endonucleolytic RNA cleavage; intron-encoded snoRNA; nonsense-mediated decay; regulation of snoRNA expression; snoRNA host genes