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DNA Methylation

DNA methylation is a covalent modification of cytosine that occurs predominantly in CpG dinucleotides.  So-called “CpG islands”, or regions of DNA enriched for CpGs are typically found near the transcriptional start sites of genes.  Methylation within a CpG island often correlates with altered expression of the associated gene, typically but not always leading to loss of transcription.  A hallmark of oncogenesis is a progressive hypermethylation of CpG islands in combination with a progressive of hypomethylation of intergenic DNA.

DNA methylation is an active and onoing process that must be maintained at each cell division.  The establishment and maintenance of DNA methylation is coordinated by special enzymes called DNA methyltransferases.  The covalent nature of DNA methylation means that this epigenetic alteration can be reversed.  Our goal is to identify small molecules that inhibit DNA methyltransferases specifically so that the disease process can be reversed.  Our validated modeling and screening procedure serves as the basis for our rational and targeted drug development (1).

  1. Siedlecki P, Boy RG, Musch T, Bruekner B, Suhai S, Lyko F, Zielenkiewicz P. Discovery of two novel, small-molecule inhibitors of DNA methylation. J Med Chem. 2006; 49(2): 678-683.