Two ribosome recruitment sites direct multiple translation events within HIV1 Gag open reading frame

Jules Deforges 1 Sylvain De Breyne 2 Melissa Ameur 1 Nathalie Ulryck 1 Nathalie Chamond 1 Afaf Saaidi 3, 4, 5 Yann Ponty 3, 4, 5 Théophile Ohlmann 2 Bruno Sargueil 1
4 AMIB - Algorithms and Models for Integrative Biology
LIX - Laboratoire d'informatique de l'École polytechnique [Palaiseau], LRI - Laboratoire de Recherche en Informatique, UP11 - Université Paris-Sud - Paris 11, Inria Saclay - Ile de France
Abstract : In the late phase of the HIV virus cycle, the full length unspliced genomic RNA is exported to the cytoplasm and serves as mRNA to translate the Gag and Gag-pol polyproteins. Three different translation initiation mechanisms responsible for Gag production have been described. However a rationale for the involvement of as many translation pathways in gRNA translation is yet to be defined. The Gag-IRES has the singularity to be located within the Gag open reading frame and to directly recruit the 40S ribosomal subunit. To further characterize this interaction, we first probed the Gag-IRES RNA structure. We then developed an innovative integrative modelling approach and propose a novel secondary structure model for the Gag-IRES. The minimal 40S ribosomal subunit binding site was further mapped using different assays. To our surprise, we found that at least two regions within Gag-IRES can independently recruit the ribosome. Next, we validated that these two regions influence Gag translation both in vitro and in cellulo. These binding sites are mostly unstructured and highly A-rich, such sequences have previously been shown to be sufficient to recruit the ribosome and to support an IRES function. A combination of biochemical and functional data give insight into the Gag-IRES molecular mechanism and provide compelling evidences for its importance. Hypothesis about its physiological role reflecting its conservation amongst primate lentiviruses are proposed.
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Nucleic Acids Research, Oxford University Press, 2017, 45 (12), pp.7382--7400. 〈https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx303〉. 〈10.1093/nar/gkx303〉
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Jules Deforges, Sylvain De Breyne, Melissa Ameur, Nathalie Ulryck, Nathalie Chamond, et al.. Two ribosome recruitment sites direct multiple translation events within HIV1 Gag open reading frame. Nucleic Acids Research, Oxford University Press, 2017, 45 (12), pp.7382--7400. 〈https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx303〉. 〈10.1093/nar/gkx303〉. 〈hal-01505282〉

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