Modified oligonucleotides as bona fide antagonists of proteins interacting with DNA: Hairpin antagonists of the human DNA methyltransferase

Pascal Bigey, J. David Knox, Sylvie Croteau, Sanjoy K. Bhattacharya, Johanne Théberge, Moshe Szyf

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The study of the biological role of DNA methyltransferase (DNA MeTase) has been impeded by the lack of direct and specific inhibitors. This report describes the design of potent DNA based antagonists of DNA MeTase and their utilization to define the interactions of DNA MeTase with its substrate and to study its biological role. We demonstrate that the size, secondary structure, hemimethylation, and phosphorothioate modification strongly affect the antagonists interaction with DNA MeTase whereas base substitutions do not have a significant effect. To study whether DNA MeTase is critical for cellular transformation, human lung non-small carcinoma cells were treated with the DNA MeTase antagonists. Ex vivo, hairpin inhibitors of DNA MeTase are localized to the cell nucleus in lung cancer cells. They inhibit DNA MeTase, cell growth, and anchorage independent growth (an indicator of tumorigenesis in cell culture) in a dose-dependent manner. The inhibitors developed in this study are the first documented example of direct inhibitors of DNA MeTase in living cells and of modified oligonucleotides as bona fide antagonists of critical cellular proteins.

Original languageEnglish (US)
Pages (from-to)4594-4606
Number of pages13
JournalJournal of Biological Chemistry
Volume274
Issue number8
DOIs
StatePublished - Feb 19 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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