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Rôle de l’activation chronique de la voie NF-kB induite par l’oncoprotéine Tax du virus HTLV-1 dans la régulation de l’épissage alternatif

Abstract : The NF-kB (nuclear factor kB) signaling pathway regulates gene transcription of genes involved in immune response and inflammation. Chronic activation of NF-kB frequently associated with inflammatory disorders and cancer. The functional impacts of NF-kB have long been studied at the promoter level. Nevertheless, recent studies of the chromatin distribution of RelA indicate that this NF-kB subunit is predominantly localized in intragenic regions, including exons and introns, where its functions remain unknown. My work has addressed this question in the context of HTLV-1 infection, which is a constitutive activator of NF-kB, and the causative agent of the Adult T-cell Leukemia. The results show that the activation of NF-kB by the viral oncoprotein Tax results in changes in alternative splicing regulations of GC-rich exons that coincide with the chromatin recruitment of RelA in the vicinity of these exons. Integrative analysis of RNA splicing and chromatin occupancy, combined with experimental chromatin tethering assays (TALE) demonstrate that the intragenic binding of RelA leads to the recruitment of the splicing regulator DDX17, which modulates the inclusion rate of exon thanks to its helicase activity. Altogether, these data reveal that, besides its transcriptional role, NF-kB RelA acts as a chromatin anchor for the splicing factor DDX17 and provides alternative splicing specificity. These data revisit our knowledge of the physiopathologic mechanisms of HTLV-1 associated diseases , as well as other disorders related to the chronic activation of the NF-kB pathway
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Lamya Ben Ameur. Rôle de l’activation chronique de la voie NF-kB induite par l’oncoprotéine Tax du virus HTLV-1 dans la régulation de l’épissage alternatif. Génétique. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1136⟩. ⟨tel-02528822⟩

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