Investigating the Inhibition of FTSJ1 a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

Pietro Salvatore Carollo; Marco Tutone; Giulia Culletta; Ignazio Fiduccia; Federica Corrao; Ivana Pibiri; Aldo Di Leonardo; Maria Grazia Zizzo; Raffaella Melfi; Andrea Pace; Anna Maria Almerico; Laura Lentini

doi:10.20944/preprints202304.0601.v1

A peer-reviewed article of this Preprint also exists.

Carollo, P.S.; Tutone, M.; Culletta, G.; Fiduccia, I.; Corrao, F.; Pibiri, I.; Di Leonardo, A.; Zizzo, M.G.; Melfi, R.; Pace, A.; Almerico, A.M.; Lentini, L. Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR. Int. J. Mol. Sci. 2023, 24, 9609. Carollo, P.S.; Tutone, M.; Culletta, G.; Fiduccia, I.; Corrao, F.; Pibiri, I.; Di Leonardo, A.; Zizzo, M.G.; Melfi, R.; Pace, A.; Almerico, A.M.; Lentini, L. Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR. Int. J. Mol. Sci. 2023, 24, 9609.

Abstract

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10% of the CFTR gene mutations are "stop" mutations, which generate a Premature Termination Codon (PTC), thus synthesizing a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, which is the ribosome’s capacity to skip a PTC, thus generating a full-length protein. “TRIDs” are molecules exerting ribosome readthrough; for some, the mechanism of action is still under debate. We investigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their readthrough activity by in silico analysis and in vitro studies. Our results suggest a likely inhibition of FTSJ1, a tryptophan tRNA-specific 2’-O-methyltransferase.

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Investigating the Inhibition of FTSJ1 a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

Abstract

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Subject

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