DHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity

Amandine Duchemin (1) , Tina O’grady (1) , Sarah Hanache (1) , Agnès Méreau (2) , Marc Thiry (1) , Ludivine Wacheul (3) , Catherine Michaux (4) , Eric Perpète (4) , Eric Hervouet (5) , Paul Peixoto (5) , Felix G M Ernst (3) , Yann Audic (2) , Franck Dequiedt (1) , Denis L J Lafontaine (3) , Denis Mottet (1)

1 GIGA [Université Liège]
2 IGDR - Institut de Génétique et Développement de Rennes
3 ULB - Université libre de Bruxelles
4 UNamur - Université de Namur [Namur]
5 RIGHT - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)

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 assembly, identifying TFIP11 as a critical spliceosome assembly regulator.

Domaines: Cancer; Organisation et fonctions cellulaires [q-bio.SC]

Amandine Duchemin, Tina O’grady, Sarah Hanache, Agnès Méreau, Marc Thiry, et al.. DHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity. Nature Communications, 2021, 12 (1), pp.6648. ⟨10.1038/s41467-021-26932-2⟩. ⟨hal-03442150⟩