The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.

Lentini, L., Melfi, R., Cancemi, P., Pibiri, I., Di Leonardo, A. (2019). Caffeine boosts Ataluren's readthrough activity. HELIYON, 5(6), 1-6 [10.1016/j.heliyon.2019.e01963].

Caffeine boosts Ataluren's readthrough activity

Lentini, Laura
;
Melfi, Raffaella;Cancemi, Patrizia;Pibiri, Ivana;Di Leonardo, Aldo
2019-06-21

Abstract

The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.
Settore BIO/06 - Anatomia Comparata E Citologia
Settore BIO/11 - Biologia Molecolare
Settore BIO/18 - Genetica
Settore CHIM/06 - Chimica Organica
https://www.sciencedirect.com/science/article/pii/S2405844019355744?via=ihub
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595402/
Lentini, L., Melfi, R., Cancemi, P., Pibiri, I., Di Leonardo, A. (2019). Caffeine boosts Ataluren's readthrough activity. HELIYON, 5(6), 1-6 [10.1016/j.heliyon.2019.e01963].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/379028
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