title: The SMG5-SMG7 heterodimer directly recruits the CCR4-NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2.
abstract: Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control mechanism that detects aberrant mRNAs containing nonsense codons and induces their rapid degradation. This degradation is mediated by SMG6, an NMD-specific endonuclease, as well as the SMG5 and SMG7 proteins, which recruit general mRNA decay enzymes. However, it remains unknown which specific decay factors are recruited and whether this recruitment is direct. Here, we show that SMG7 binds directly to POP2, a catalytic subunit of the CCR4-NOT deadenylase complex, and elicits deadenylation-dependent decapping and 5'-to-3' decay of NMD targets. Accordingly, a catalytically inactive POP2 mutant partially suppresses NMD in human cells. The SMG7-POP2 interaction is critical for NMD in cells depleted of SMG6, indicating that SMG7 and SMG6 act redundantly to promote the degradation of NMD targets. We further show that UPF1 provides multiple binding sites for decapping factors. These data unveil a missing direct physical link between NMD and the general mRNA decay machinery and indicate that NMD employs diverse and partially redundant mechanisms to ensure robust degradation of aberrant mRNAs.
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Belinda
authors.initials: B
authors.lastname: Loh
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jonas
authors.forename: Elisa
authors.initials: E
authors.lastname: Izaurralde
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D018389:Codon, Nonsense / Q000378:metabolism*; D019281:Dimerization; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C515354:CCR4 protein, human; C489780:CNOT8 protein, human; D002352:Carrier Proteins; D018389:Codon, Nonsense; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D021122:Protein Subunits; D012333:RNA, Messenger; D054398:Receptors, CCR4; D014157:Transcription Factors
keywords: NMD; UPF1; deadenylation; mRNA decay