Polyamines, DNA methylation and cell differentiation.

The cellular concentration of AdoMet is normally very much higher than that of dcAdoMet, the aminopropyl group donor in polyamine synthesis. However, when cells are depleted of their putrescine and spermidine, i.e. the aminopropyl group acceptors, the dcAdoMet concentration increases dramatically, to a level that may greatly exceed that of AdoMet. Using a highly purified DNA methyltransferase and its preferred substrates, a defined hemimethylated duplex oligodeoxynucleotide or poly(dI-dC)-poly(dI-dC), we demonstrate that dcAdoMet is a poor methyl group donor, and that it starts to inhibit DNA methylation when its concentration exceeds that of AdoMet. At a dcAdoMet/AdoMet ratio of 5:1 there is very little methyl transfer. This study suggests that the antiproliferative and differentiative effects brought about by inhibitors of polyamine synthesis may be partly attributable to dcAdoMet-mediated inhibition of DNA methylation.