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

Amandine Duchemin, Tina O’Grady, Sarah Hanache, Agnès Mereau, Marc Thiry, Ludivine Wacheul, Catherine Michaux, Eric Perpète, Eric Hervouet, Paul Peixoto, Felix G. M. Ernst, Yann Audic, Franck Dequiedt, Denis L. J. Lafontaine and Denis Mottet ()
Additional contact information
Amandine Duchemin: University of Liege
Tina O’Grady: University of Liege
Sarah Hanache: University of Liege
Agnès Mereau: Université de Rennes
Marc Thiry: University of Liege
Ludivine Wacheul: Université Libre de Bruxelles (ULB) - Biopark campus Gosselies
Catherine Michaux: University of Namur
Eric Perpète: University of Namur
Eric Hervouet: University Bourgogne Franche-Comté
Paul Peixoto: University Bourgogne Franche-Comté
Felix G. M. Ernst: Université Libre de Bruxelles (ULB) - Biopark campus Gosselies
Yann Audic: Université de Rennes
Franck Dequiedt: University of Liege
Denis L. J. Lafontaine: Université Libre de Bruxelles (ULB) - Biopark campus Gosselies
Denis Mottet: University of Liege

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26932-2

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