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Nouvel aperçu des partenaires moléculaires des snoRNP à boîtes C/D et des fonctions biologiques associées

Abstract : The human genome contains more than two hundred C/D box small nucleolar RNAs (snoRNAs) genes. C/D snoRNAs associate with a set of four core proteins to catalyze 2ʹ-O-methylations of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). Interestingly, over the past decade, studies done mostly on mammalian models suggested that snoRNPs are involved in unrelated cellular processes. The human genome encodes numerous orphan C/D snoRNAs that do not possess obvious complementarities with canonical target RNAs. Also, several lines of evidence pointed to the possibility that snoRNAs associate with other proteins than snoRNP core proteins and may affect cell metabolism and proliferation. Finally, specific snoRNAs are deregulated in pathologies such as the Prader-Willi syndrome or in several cancers. In front of this initially unsuspected complex picture, we emit the hypothesis that the formation, the fate, and the functions of snoRNPs are regulated by unappreciated protein factors, in physiological and pathological contexts. Thus, our main objectives were to study new molecular mechanisms involved in C/D box snoRNPs functions using a combination of several complementary approaches, based on the study of RNA:protein and RNA:RNA interactions. We identified that the orphan snoRNA SNORD116 possesses a complementarity antisense element with several mRNAs sequences and we observed that the depletion of SNORD116 by ASO affects their steady state levels. We searched for new snoRNP protein partners by a combination of co-immunoprecipitation (IP) and mass spectrometry (MS) analyses. We identified that GNL3/Nucleostemin, a GTP-binding protein interacts with protein complexes involved in C/D snoRNP biogenesis. We also identified that the RNA binding protein ILF3 interacts with mature snoRNPs. Depletion of ILF3 by siRNAs does not affect snoRNA steady state levels and modestly modulates their association with the ribosome. Analysis of rRNAs 2ʹ-O-methylations will be crucial to determine whether ILF3 affects snoRNPs catalytic activities. Moreover, data obtained from IP-MS and CLIP (crosslinking immunoprecipitation)-microarray suggested that ILF3 impacts the association of snoRNPs with the splicing machinery which leads to a change in the splicing pattern of several cellular mRNAs.
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Submitted on : Tuesday, June 29, 2021 - 5:39:25 PM
Last modification on : Saturday, October 16, 2021 - 11:20:03 AM

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Laeya Baldini. Nouvel aperçu des partenaires moléculaires des snoRNP à boîtes C/D et des fonctions biologiques associées. Biochimie, Biologie Moléculaire. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0009⟩. ⟨tel-03274102⟩



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