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Etudes fonctionnelles sur les composants de la voie des piRNAs MOV10L1 et FKBP6

Abstract : Piwi-interacting RNAs (piRNAs) associate to members of the PIWI clade of Argonaute proteins and are responsible for silencing of transposable elements in animal germ lines. In mouse, PIWI proteins mediate DNA methylation at the level of transposon promoters and are required for male fertility. piRNAs are produced through two biogenesis pathways, known as primary processing and ping-pong amplification cycle. This study focuses on the functions of two PIWI-associated proteins: the putative RNA helicase MOV10L1 and the immunophilin FKBP6. Here, the role of MOV10L1 as a primary piRNA processing factor is described. Genetic disruption of MOV10L1's RNA helicase domain results in male-specific sterility and derepression of retrotransposons due to reduction of DNA methylation. A complete loss of piRNAs is observed in the mutant, pointing to a pivotal role of MOV10L1 in piRNA biogenesis. Tdrd1 associates with PIWI proteins and has been suggested to play a role in the piRNA pathway by recruiting some factor through its N-terminal MYND domain. We show that Tdrd1's MYND domain interacts with FKBP6, which belongs to a family of prolyl isomerases present in chaperone complexes. Biochemical studies suggest FKBP6 is inactive and uses its prolyl isomerase domain as a structural module for binding PIWI proteins, while binding Hsp90 through its TPR domain. Analysis of an fkbp6 mutant mouse reveals transposon derepression and loss of DNA methylation, but little defects in primary piRNA biogenesis. These results are consistent with a role of FKBP6 downstream of Tdrd1, and we speculate that it might recruit Hsp90 to PIWI complexes to mediate ping-pong amplification cycle.
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https://tel.archives-ouvertes.fr/tel-00664995
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Jordi Xiol. Etudes fonctionnelles sur les composants de la voie des piRNAs MOV10L1 et FKBP6. Autre [q-bio.OT]. Université de Grenoble, 2011. Français. ⟨NNT : 2011GRENV026⟩. ⟨tel-00664995⟩

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