Targeting FTSJ1 to Restore TP53 Function in Nonsense Mutation-Driven Cancer: Computational and Experimental Evaluation of 1,2,4-Triazole Derivatives
- 1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 11, 90123 Palermo, Italy
Abstract
Nonsense mutations introduce premature termination codons (PTCs) into mRNA transcripts, leading to truncated and non-functional proteins, and accounting for approximately 10–15% of genetic disorders. In this context, the induction of translational readthrough by small molecules, known as translational readthrough-inducing drugs (TRIDs), has emerged as a promising therapeutic strategy to restore full-length protein expression. However, the mechanism of action of TRIDs is still under debate, and one emerging target is FTSJ1, a methyltransferase involved in tRNA modification. FTSJ1 regulates translational fidelity and nonsense-mediated mRNA decay, and its inhibition has been proposed to facilitate the restoration of full-length proteins from nonsense-mutated genes. In this study, we investigated the inhibition of FTSJ1 methyltransferase by a novel series of TRIDs, the 1,2,4-triazole derivatives IP14, IP15, IP17, and IP18, using a luciferase assay in HeLa cells transfected with the pFLuc190UGA plasmid, which in our previous studies showed the rescue of p53 expression in H1299 R213X cells with TP53 gene harboring the R213X nonsense mutation. An integrated computational workflow, including induced fit docking, binding pose metadynamics, molecular dynamics simulations, and MM-GBSA analysis, was employed to characterize their interaction within the FTSJ1 catalytic pocket. The computational results revealed stable binding modes and favorable energetic profiles, supporting the hypothesis that inhibition of FTSJ1 may contribute to their biological activity. Consistent with these findings, in vitro assays supported their translational readthrough activity, suggesting a possible mechanism of action.
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BibTeX
@article{roomi2026targeting,
title = {{Targeting FTSJ1 to Restore TP53 Function in Nonsense Mutation-Driven Cancer: Computational and Experimental Evaluation of 1,2,4-Triazole Derivatives}},
author = {Muhammad Sohaib Roomi and Giulia Culletta and Vincenzo Lombardo and Emanuele Vitale and Davide Ricci and Riccardo Varrica and Ignazio Fiduccia and Andrea Pace and Laura Lentini and Ivana Pibiri and Marco Tutone},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203709},
url = {https://www.mdpi.com/1420-3049/31/20/3709},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting FTSJ1 to Restore TP53 Function in Nonsense Mutation-Driven Cancer: Computational and Experimental Evaluation of 1,2,4-Triazole Derivatives
AU - Muhammad Sohaib Roomi
AU - Giulia Culletta
AU - Vincenzo Lombardo
AU - Emanuele Vitale
AU - Davide Ricci
AU - Riccardo Varrica
AU - Ignazio Fiduccia
AU - Andrea Pace
AU - Laura Lentini
AU - Ivana Pibiri
AU - Marco Tutone
PY - 2026
DA - 2026/10/16
JO - Molecules
DO - 10.3390/molecules31203709
UR - https://www.mdpi.com/1420-3049/31/20/3709
AB - Nonsense mutations introduce premature termination codons (PTCs) into mRNA transcripts, leading to truncated and non-functional proteins, and accounting for approximately 10–15% of genetic disorders. In this context, the induction of translational readthrough by small molecules, known as translational readthrough-inducing drugs (TRIDs), has emerged as a promising therapeutic strategy to restore full-length protein expression. However, the mechanism of action of TRIDs is still under debate, and one emerging target is FTSJ1, a methyltransferase involved in tRNA modification. FTSJ1 regulates translational fidelity and nonsense-mediated mRNA decay, and its inhibition has been proposed to facilitate the restoration of full-length proteins from nonsense-mutated genes. In this study, we investigated the inhibition of FTSJ1 methyltransferase by a novel series of TRIDs, the 1,2,4-triazole derivatives IP14, IP15, IP17, and IP18, using a luciferase assay in HeLa cells transfected with the pFLuc190UGA plasmid, which in our previous studies showed the rescue of p53 expression in H1299 R213X cells with TP53 gene harboring the R213X nonsense mutation. An integrated computational workflow, including induced fit docking, binding pose metadynamics, molecular dynamics simulations, and MM-GBSA analysis, was employed to characterize their interaction within the FTSJ1 catalytic pocket. The computational results revealed stable binding modes and favorable energetic profiles, supporting the hypothesis that inhibition of FTSJ1 may contribute to their biological activity. Consistent with these findings, in vitro assays supported their translational readthrough activity, suggesting a possible mechanism of action.
SN - 1420-3049
ER -