title: The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex.
abstract: Nonsense-mediated decay (NMD) is a surveillance mechanism that degrades aberrant mRNAs. A complex comprising SMG1, UPF1, and the translation termination factors eRF1 and eRF3 (SURF) is assembled in the vicinity of a premature termination codon. Subsequently, an interaction with UPF2, UPF3b, and the exon junction complex induces the formation of the decay-inducing complex (DECID) and triggers NMD. We previously identified the RNA helicase DHX34 as an NMD factor in C. elegans and in vertebrates. Here, we investigate the mechanism by which DHX34 activates NMD in human cells. We show that DHX34 is recruited to the SURF complex via its preferential interaction with hypophosphorylated UPF1. A series of molecular transitions induced by DHX34 include enhanced recruitment of UPF2, increased UPF1 phosphorylation, and dissociation of eRF3 from UPF1. Thus, DHX34 promotes mRNP remodeling and triggers the conversion from the SURF complex to the DECID complex resulting in NMD activation.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Nele
authors.initials: N
authors.lastname: Hug
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. Electronic address: javier.caceres@igmm.ed.ac.uk.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Cáceres
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D010454:Peptide Termination Factors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: C489002:ETF1 protein, human; D010454:Peptide Termination Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D015534:Trans-Activators; D014157:Transcription Factors; C468286:UPF2 protein, human; C026452:messenger ribonucleoprotein; C087971:peptide-chain-release factor 3; C559844:DHX34 protein, human; D020365:RNA Helicases; C101828:UPF1 protein, human