Journal
MOLECULAR BIOLOGY
Volume 43, Issue 3, Pages 418-425Publisher
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S0026893309030108
Keywords
human DNA methyltransferase 1; oligodeoxyribonucleotides; enzyme-substrate interaction; enzyme inhibition
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Funding
- International Science and Technology Center [3312]
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Mammalian DNA methyltransferase 1 (Dnmt1) is responsible for copying the DNA methylation pattern during cell division. Since Dnmt1 plays an important role in carcinogenesis, it is of particular interest to search for its specific inhibitors. To design oligonucleotide inhibitors of human Dnmt1, a number of singlestranded, double-stranded, and hairpin DNA structures containing a canonical or a modified Dnmt1 recognition site (5'-CG) were constructed on the basis of a 22-nt sequence. Structural features such as a C:A mismatch, phosphorothioates, and hairpins proved capable of incrementally increasing the oligonucleotide affinity for Dnmt1. An improvement of inhibitory properties was also achieved by replacing the target cytosine with 5,6-dihydro-5-azacytosine, 5-methyl-2-pyrimidinone, or 6-methyl-pyrrolo-[2,3-d]-2-pyrimidinone. The concentration that caused 50% inhibition of methylation of 1 mu M poly(dI-dC) center dot poly(dI-dC), a conventional DNA substrate, was approximately 10(-7) M for the most efficient oligonucleotides. Under the same in vitro conditions, these oligonucleotide inhibitors demonstrated a substantially stronger effect compared to known Dnmt1 inhibitors, which were used as controls.
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