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A new link between translation termination and NMD complexes

Abstract : Premature termination codons (PTCs) account for approximately one third of inherited and acquired diseases. A surveillance pathway called nonsense-mediated mRNA decay (NMD) detects and degrades PTC-containing transcripts. NMD core factors UPF1, UPF2 and UPF3 mediate the recognition of PTCs by associating with the terminating translation machinery composed of the ribosome, the release factors eRF1 and eRF3 and the poly(A) binding protein (Pab1p in yeast). Using electron cryo-microscopy, we solved such a complex in yeast and observed the translating ribosome, containing a P-site tRNA and an A-site density for the release factors but not for Pab1p indicating that Pab1p is flexibly bound. We also probed the function of NMD factors in mammalian termination using a reconstituted human in vitro translation system. Surprisingly, we found that UPF3B delayed stop codon recognition and promoted ribosomal dissociation. The addition of UPF2 could abolish UPF3B’s effect on translation termination. UPF1 had no influence in the termination process alone or in combination with UPF2. Using in vitro and in vivo pulldowns we found that UPF3B interacts with eRF3a and UPF1, indicating that UPF3B could be the missing link between termination and NMD. Our results point to a complex interplay between the NMD factors and the termination apparatus.
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https://tel.archives-ouvertes.fr/tel-01784960
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Submitted on : Friday, May 4, 2018 - 1:01:49 AM
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  • HAL Id : tel-01784960, version 1

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Etienne Raimondeau. A new link between translation termination and NMD complexes. Biochemistry, Molecular Biology. Université Grenoble Alpes, 2016. English. ⟨NNT : 2016GREAV048⟩. ⟨tel-01784960⟩

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