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Structural and Functional Insights into Saccharomyces cerevisiae Tpa1, a Putative Prolylhydroxylase Influencing Translation Termination and Transcription

Abstract : Efficiency of translation termination relies on the specific recognition of the three stop codons by the eukaryotic translation termination factor eRF1. To date only a few proteins are known to be involved in translation termination in eukaryotes. Saccharomyces cerevisiae Tpa1, a largely conserved but uncharacterized protein, has been described to associate with a messenger ribonucleoprotein complex located at the 3 end of mRNAs that contains at least eRF1, eRF3, and Pab1. Deletion of the TPA1 gene results in a decrease of translation termination efficacy and an increase in mRNAs half-lives and longer mRNA poly(A) tails. In parallel, Schizosaccharomyces pombe Ofd1, a Tpa1 ortholog, and its partner Nro1 have been implicated in the regulation of the stability of a transcription factor that regulates genes essential for the cell response to hypoxia. To gain insight into Tpa1/ Ofd1 function, we have solved the crystal structure of S. cerevisiae Tpa1 protein. This protein is composed of two equivalent domains with the double-stranded ␤-helix fold. The N-terminal domain displays a highly conserved active site with strong similarities with prolyl-4-hydroxylases. Further functional studies show that the integrity of Tpa1 active site as well as the presence of Yor051c/Ett1 (the S. cerevisiae Nro1 ortholog) are essential for correct translation termination. In parallel, we show that Tpa1 represses the expression of genes regulated by Hap1, a transcription factor involved in the response to levels of heme and oxygen. Altogether, our results support that Tpa1 is a putative enzyme acting as an oxygen sensor and influencing several distinct regulatory pathways.
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https://hal.archives-ouvertes.fr/hal-03298541
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Submitted on : Friday, July 23, 2021 - 4:49:33 PM
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Julien Henri, Delphine Rispal, Emilie Bayart, Herman van Tilbeurgh, Bertrand Séraphin, et al.. Structural and Functional Insights into Saccharomyces cerevisiae Tpa1, a Putative Prolylhydroxylase Influencing Translation Termination and Transcription. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2010, 285 (40), pp.30767 - 30778. ⟨10.1074/jbc.m110.106864⟩. ⟨hal-03298541⟩

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