title: Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways.
abstract: Besides degrading aberrant mRNAs that harbor a premature translation termination codon (PTC), nonsense-mediated mRNA decay (NMD) also targets many seemingly "normal" mRNAs that encode for full-length proteins. To identify a bona fide set of such endogenous NMD targets in human cells, we applied a meta-analysis approach in which we combined transcriptome profiling of knockdowns and rescues of the three NMD factors UPF1, SMG6, and SMG7. We provide evidence that this combinatorial approach identifies NMD-targeted transcripts more reliably than previous attempts that focused on inactivation of single NMD factors. Our data revealed that SMG6 and SMG7 act on essentially the same transcripts, indicating extensive redundancy between the endo- and exonucleolytic decay routes. Besides mRNAs, we also identified as NMD targets many long noncoding RNAs as well as miRNA and snoRNA host genes. The NMD target feature with the most predictive value is an intron in the 3' UTR, followed by the presence of upstream open reading frames (uORFs) and long 3' UTRs. Furthermore, the 3' UTRs of NMD-targeted transcripts tend to have an increased GC content and to be phylogenetically less conserved when compared to 3' UTRs of NMD insensitive transcripts.
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland.|Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, CH-3012 Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Martino
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Karousis
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Joël
authors.initials: J
authors.lastname: Bourquin
authors.affiliation: Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bruggmann
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mühlemann
mesh_terms: D001482:Base Composition; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018389:Codon, Nonsense; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism; D059365:Nonsense Mediated mRNA Decay; D011485:Protein Binding; D020365:RNA Helicases; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000737:chemistry / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D004722:Endoribonucleases
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D035683:MicroRNAs; D020365:RNA Helicases; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020537:RNA, Small Nucleolar; D019098:Telomerase; D015534:Trans-Activators; C494578:SMG7 protein, human; C512261:SMG6 protein, human; D004722:Endoribonucleases; C101828:UPF1 protein, human
keywords: RNA turnover; SMG6; SMG7; UPF1; bioinformatics analysis; mRNA-seq; nonsense-mediated mRNA decay; post-transcriptional gene regulation