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Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay.

Cell | Apr 18, 2008

In mammalian cells, nonsense-mediated mRNA decay (NMD) generally requires that translation terminates sufficiently upstream of a post-splicing exon junction complex (EJC) during a pioneer round of translation. The subsequent binding of Upf1 to the EJC triggers Upf1 phosphorylation. We provide evidence that phospho-Upf1 functions after nonsense codon recognition during steps that involve the translation initiation factor eIF3 and mRNA decay factors. Phospho-Upf1 interacts directly with eIF3 and inhibits the eIF3-dependent conversion of 40S/Met-tRNA(i)(Met)/mRNA to translationally competent 80S/Met-tRNA(i)(Met)/mRNA initiation complexes to repress continued translation initiation. Consistent with phospho-Upf1 impairing eIF3 function, NMD fails to detectably target nonsense-containing transcripts that initiate translation independently of eIF3 from the CrPV IRES. There is growing evidence that translational repression is a key transition that precedes mRNA delivery to the degradation machinery. Our results uncover a critical step during NMD that converts a pioneer translation initiation complex to a translationally compromised mRNP.

Pubmed ID: 18423202 RIS Download

Mesh terms: Animals | COS Cells | Cercopithecus aethiops | Codon, Nonsense | HeLa Cells | Hepacivirus | Humans | Phosphorylation | Protein Biosynthesis | RNA Stability | RNA, Messenger | Ribonucleoproteins | Trans-Activators

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM073732
  • Agency: NIGMS NIH HHS, Id: R01 GM074593
  • Agency: NIGMS NIH HHS, Id: P01 GM073732
  • Agency: NIGMS NIH HHS, Id: R37 GM074593
  • Agency: NIGMS NIH HHS, Id: GM074593

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