Alteration of enzymatic DNA methylation by chemical carcinogens.

Abstract

It is generally accepted that the DNA methylation pattern in a particular cell type is stable over the cell generations and is clonally inherited by a semiconservative mechanism in which the methylation of the progeny strand is determined by the 5-methylcytosine residue present in the parental strand. In our experiments, we have been able to show that the chemical carcinogens MNU, MNNG, and L-ethionine affect the methylation process either by modification of the DNA substrate or by interference at the cofactor level. The changes introduced into the cellular methylation pattern persist and are inherited in the progeny cells regardless of whether the carcinogens or their adducts in the DNA persist in the cell or not. The carcinogen-induced hypomethylation correlates with the increased transcriptional complexity of the nRNA of treated cells, indicating the initiation of transcription at sites previously inactive. This means that chemical carcinogens can cause, by interference with the process of DNA methylation, stable changes in the program of genetic expression; the possibility that such changes are related to the process of initiation of carcinogenesis should not be overlooked.