title: ATP hydrolysis by UPF1 is required for efficient translation termination at premature stop codons.
abstract: Nonsense-mediated mRNA decay (NMD) represents a eukaryotic quality control pathway that recognizes and rapidly degrades transcripts harbouring nonsense mutations to limit accumulation of non-functional and potentially toxic truncated polypeptides. A critical component of the NMD machinery is UPF1, an RNA helicase whose ATPase activity is essential for NMD, but for which the precise function and site of action remain unclear. We provide evidence that ATP hydrolysis by UPF1 is required for efficient translation termination and ribosome release at a premature termination codon. UPF1 ATPase mutants accumulate 3' RNA decay fragments harbouring a ribosome stalled during premature termination that impedes complete degradation of the mRNA. The ability of UPF1 to impinge on premature termination, moreover, requires ATP-binding, RNA-binding and NMD cofactors UPF2 and UPF3. Our results reveal that ATP hydrolysis by UPF1 modulates a functional interaction between the NMD machinery and terminating ribosomes necessary for targeting substrates to accelerated degradation.
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Lucas D
authors.initials: LD
authors.lastname: Serdar
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: DaJuan L
authors.initials: DL
authors.lastname: Whiteside
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Kristian E
authors.identifier: http://orcid.org/0000-0003-2262-5434
authors.initials: KE
authors.lastname: Baker
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D018389:Codon, Nonsense / Q000235:genetics*; D006868:Hydrolysis; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010443:Peptide Chain Termination, Translational; D011132:Polyribosomes / Q000378:metabolism; D020365:RNA Helicases / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C074151:NAM7 protein, S cerevisiae; D020365:RNA Helicases