4.8 Article

2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations

Journal

NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15140-z

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Funding

  1. Vaincre la mucoviscidose
  2. Association francaise contre les myopathies
  3. GIP Canceropole Nord Ouest
  4. Fondation Maladies Rares
  5. SATT Lutech

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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 tRNA(Trp). 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. p id=Par Nonsense mutations can be corrected by several molecules that activate readthrough of premature termination codon. Here, the authors report that 2,6-diaminopurine efficiently corrects UGA nonsense mutations with no significant toxicity.

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