Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

TY - JOUR

T1 - Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

AU - Lykke-Andersen, Søren

AU - Chen, Yun

AU - Ardal, Britt

AU - Lilje, Berit

AU - Waage, Johannes Eichler

AU - Sandelin, Albin Gustav

AU - Jensen, Torben Heick

N1 - © 2014 Lykke-Andersen et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2014/11/15

Y1 - 2014/11/15

N2 - 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.

AB - 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.

U2 - 10.1101/gad.246538.114

DO - 10.1101/gad.246538.114

M3 - Journal article

C2 - 25403180

SN - 0890-9369

VL - 28

SP - 2498

EP - 2517

JO - Genes & Development

JF - Genes & Development

ER -