title: SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan.
abstract: Messenger RNAs harboring nonsense codons (or premature translation termination codons [PTCs]) are degraded by a conserved quality-control mechanism known as nonsense-mediated mRNA decay (NMD), which prevents the accumulation of truncated and potentially harmful proteins. In Drosophila melanogaster, degradation of PTC-containing messages is initiated by endonucleolytic cleavage in the vicinity of the nonsense codon. The endonuclease responsible for this cleavage has not been identified. Here, we show that SMG6 is the long sought NMD endonuclease. First, cells expressing an SMG6 protein mutated at catalytic residues fail to degrade PTC-containing messages. Moreover, the SMG6-PIN domain can be replaced with the active PIN domain of an unrelated protein, indicating that its sole function is to provide endonuclease activity for NMD. Unexpectedly, we found that the catalytic activity of SMG6 contributes to the degradation of PTC-containing mRNAs in human cells. Thus, SMG6 is a conserved endonuclease that degrades mRNAs terminating translation prematurely in metazoa.
authors.affiliation: Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Huntzinger
authors.forename: Isao
authors.initials: I
authors.lastname: Kashima
authors.forename: Maria
authors.initials: M
authors.lastname: Fauser
authors.forename: Jérôme
authors.initials: J
authors.lastname: Saulière
authors.forename: Elisa
authors.initials: E
authors.lastname: Izaurralde
mesh_terms: D000818:Animals; D018389:Codon, Nonsense; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D004722:Endoribonucleases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D018389:Codon, Nonsense; D029721:Drosophila Proteins; D004722:Endoribonucleases; C533899:SMG6 protein, Drosophila