Identifying Potent Nonsense-Mediated mRNA Decay Inhibitors with a Novel Screening System

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Carrard, Julie | Ratajczak, Fiona | Elsens, Joséphine | Leroy, Catherine | Kong, Rebekah | Geoffroy, Lucie | Comte, Arnaud | Fournet, Guy | Joseph, Benoît | Li, Xiubin | Moebs-Sanchez, Sylvie | Lejeune, Fabrice

Edité par CCSD ; MDPI -

International audience. Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the TP53 gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation.

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