2,6-Diaminopurine as a highly potent corrector of UGA 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 and Fabrice Lejeune ()
Additional contact information
Carole Trzaska: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies
Séverine Amand: UMR 7245 CNRS-MNHN
Christine Bailly: UMR 7245 CNRS-MNHN
Catherine Leroy: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies
Virginie Marchand: UMS2008 IBSLor CNRS-Université de Lorraine-INSERM
Evelyne Duvernois-Berthet: UMR7221 CNRS-MNHN
Jean-Michel Saliou: University of Lille
Hana Benhabiles: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies
Elisabeth Werkmeister: Cellular Microbiology and Physics of Infection Group, Center for Infection and Immunity of Lille, CNRS UMR8204, INSERM U1019, Institut Pasteur de Lille, Lille Regional Univ. Hosp. Centr., Lille Univ.
Thierry Chassat: Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale)
Romain Guilbert: Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale)
David Hannebique: Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale)
Anthony Mouray: Institut Pasteur de Lille – PLEHTA (Plateforme d’expérimentation et de Haute Technologie Animale)
Marie-Christine Copin: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies
Pierre-Arthur Moreau: LGCgE, Laboratoire de Génie Civil et géo-Environnement
Eric Adriaenssens: CANTHER – Cancer Heterogeneity, Plasticity and Résistance to Therapies
Andreas Kulozik: EMBL/Medical Faculty Molecular Medicine Partnership Unit
Eric Westhof: Institute of Molecular and Cellular Biology of the CNRS UPR9002/University of Strasbourg
David Tulasne: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies
Yuri Motorin: CNRS - Université de Lorraine
Sylvie Rebuffat: UMR 7245 CNRS-MNHN
Fabrice Lejeune: CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15140-z

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