Le lundi 30 mai 2022, Madame Sarah HANACHE subira l'examen en vue de l'obtention du grade académique de Docteur en Sciences biomédicales et pharmaceutiques sous la direction de Monsieur Denis MOTTET.

Cette épreuve consistera en la défense publique d'un mémoire intitulé :

"New role for the splicing factor TFIP11 in the regulation of spliceosome activity"

The U6 snRNA, the core catalytic component of the spliceosome, is extensively modified post-transcriptionally, with 2'-O-methylation being most common. However, how U6 2'-O-methylation is regulated remains largely unknown. Here we report that TFIP11, the human homolog of the yeast spliceosome disassembly factor Ntr1, localizes to nucleoli and Cajal Bodies and is essential for the 2'-O-methylation of U6. Mechanistically, we demonstrate that TFIP11 knockdown reduces the association of U6 snRNA with fibrillarin and associated snoRNAs, therefore altering U6 2′-O-methylation. We show U6 snRNA hypomethylation is associated with changes in assembly of the U4/U6.U5 tri-snRNP leading to defects in spliceosome assembly and alterations in splicing fidelity. Strikingly, this function of TFIP11 is independent of the RNA helicase DHX15, its known partner in yeast. In sum, our study demonstrates an unrecognized function for TFIP11 in U6 snRNP modification and U4/U6.U5 tri-snRNP stability, identifying TFIP11 as a critical spliceosome assembly regulator.

Le Jury sera composé de :

Franck Dequiedt (Président), Michaël Herfs(Secrétaire), Christophe Deroanne, Denis Mottet, Nor Eddine Sounni, Wojtek Galej (EMBL Grenoble - France), Véronique Kruys (ULB ).