6533b7d6fe1ef96bd1265c41
RESEARCH PRODUCT
Caffeine boosts Ataluren's readthrough activity
Laura LentiniIvana PibiriPatrizia CancemiAldo Di LeonardoRaffaella Melfisubject
0301 basic medicineMolecular biologymedia_common.quotation_subjectCellNonsenseNonsense mutationMRNA DecaySettore BIO/11 - Biologia MolecolareBiochemistryCystic fibrosisArticleCystic fibrosisCFTR gene03 medical and health scienceschemistry.chemical_compound0302 clinical medicineCaffeinemedicinelcsh:Social sciences (General)Settore BIO/06 - Anatomia Comparata E Citologialcsh:Science (General)media_commonMessenger RNAMultidisciplinaryNonsense mutationNonsense mutationsPTC readthroughAtaluren/PTC124Settore CHIM/06 - Chimica Organicamedicine.diseaseCell biologyAtalurenSettore BIO/18 - Genetica030104 developmental biologymedicine.anatomical_structurechemistryCystic fibrosilcsh:H1-99Caffeine030217 neurology & neurosurgerylcsh:Q1-390description
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-06-01 | Heliyon |