Published: 20 March 2020 https://doi.org/10.1038/s41467-020-15140-z
Nonsense mutations cause about 10% of genetic disease cases, and no treatments are available. Nonsense mutations can be corrected by molecules with nonsense mutation readthrough activity. An extract of the mushroom Lepista inversa has recently shown high-efficiency correction of UGA and UAA nonsense mutations. One active constituent of this extract is 2,6-diaminopurine (DAP). In Calu-6 cancer cells, in which TP53 gene has a UGA nonsense mutation, DAP treatment increases p53 level. It also decreases the growth of tumors arising from Calu-6 cells injected into immunodeficient nude mice. DAP acts by interfering with the activity of a tRNA-specific 2′-O-methyltransferase (FTSJ1) responsible for cytosine 34 modification in tRNATrp. Low-toxicity and high-efficiency UGA nonsense mutation correction make DAP a good candidate for the development of treatments for genetic diseases caused by nonsense mutations.
Carole Trzaska, Séverine Amand, Christine Bailly, Catherine Leroy, Virginie Marchand, Evelyne Duvernois-Berthet, Jean-Michel Saliou, Hana Benhabiles, Elisabeth Werkmeister, Thierry Chassat, Romain Guilbert, David Hannebique, Anthony Mouray, Marie-Christine Copin, Pierre-Arthur Moreau, Eric Adriaenssens, Andreas Kulozik, Eric Westhof, David Tulasne, Yuri Motorin, Sylvie Rebuffat & Fabrice Lejeune