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

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

doi:10.3390/ijms24119609

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…Recently, we explored the possible MOA of these molecules to identify the interaction with specific proteins involved in the translation process. Our results showed that NV914 and NV930 could interact with the FTSJ1 2′-O-methyltransferase [29].…”

Section: Introductionmentioning

confidence: 66%

“…According to the experimental evidence, NV molecules restore CFTR protein expression after the treatment of in vitro cystic fibrosis model systems and Shwachman-Diamond model systems [15,28]. Recently, we showed that two of our NV molecules, NV914 and NV930, could interact with the FTSJ1 2 -O-methyltransferase to favor the readthrough process [29].…”

Section: Discussionmentioning

confidence: 96%

“…In the last few years, three new TRIDs were identified by our group and tested to validate their translational readthrough ability and tolerability in vivo [27][28][29]. These compounds, named NV848, NV914, and NV930 (also known as NV molecules; PTC Int.…”

Section: Introductionmentioning

confidence: 99%

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Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Perriera,

Vitale,

Pibiri

et al. 2023

IJMS

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Nonsense mutations cause several genetic diseases such as cystic fibrosis, Duchenne muscular dystrophy, β-thalassemia, and Shwachman–Diamond syndrome. These mutations induce the formation of a premature termination codon (PTC) inside the mRNA sequence, resulting in the synthesis of truncated polypeptides. Nonsense suppression therapy mediated by translational readthrough-inducing drugs (TRIDs) is a promising approach to correct these genetic defects. TRIDs generate a ribosome miscoding of the PTC named “translational readthrough” and restore the synthesis of full-length and potentially functional proteins. The new oxadiazole-core TRIDs NV848, NV914, and NV930 (NV) showed translational readthrough activity in nonsense-related in vitro systems. In this work, the possible off-target effect of NV molecules on natural termination codons (NTCs) was investigated. Two different in vitro approaches were used to assess if the NV molecule treatment induces NTC readthrough: (1) a study of the translational-induced p53 molecular weight and functionality; (2) the evaluation of two housekeeping proteins’ (Cys-C and β2M) molecular weights. Our results showed that the treatment with NV848, NV914, or NV930 did not induce any translation alterations in both experimental systems. The data suggested that NV molecules have a specific action for the PTCs and an undetectable effect on the NTCs.

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Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 96%

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Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Perriera,

Vitale,

Pibiri

et al. 2023

IJMS

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show abstract

“…In another recent study, three small molecules named, NV848, NV914, and NV930 were shown to promote the readthrough activity by inhibition of FTSJ1, a tRNATrp-specific 2′-O-methyltransferase [ 122 ].…”

Section: Readthrough Mechanismmentioning

confidence: 99%

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Benslimane,

Loret,

Chazelas

et al. 2024

Pharmaceuticals

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Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.

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DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss

Martino,

Gargano,

Carollo

et al. 2024

Cell. Mol. Life Sci.

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Methylation of cytosine in CpG dinucleotides is an epigenetic modification carried out by DNA-methyltransferases (DNMTs) that contributes to chromatin condensation and structure and, thus, to gene transcription regulation and chromosome stability. DNMT1 maintains the DNA methylation pattern of the genome at each cell cycle by copying it to the newly synthesized DNA strand during the S-phase. DNMT1 pharmacological inhibition as well as genetic knockout and knockdown, leads to passive DNA methylation loss. However, these strategies have been associated with different cell fates, even in the same cell background, suggesting that they can question the interpretation of the obtained results. Using a cell system in which endogenous DNMT1 is fused with an inducible degron and can be rapidly degraded, we found that in non-tumoral RPE-1 cells, DNMT1 loss progressively induced cell proliferation slowing-down and cell cycle arrest at the G1/S transition. The latter is due to p21 activation, which is partly mediated by p53 and leads to a global reduction in DNA methylation. DNMT1 restoration rescues cell proliferation, indicating that its deregulation is sensed as tunable cellular stress. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-024-05547-y.

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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

Cited by 7 publications

References 36 publications

Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss

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