Impaired enzymatic methylation of BPDE-modified DNA.

Highly purified DNA methyltransferase from human placenta methylates hemimethylated and 5-methylcytosine-free DNA substrates suggesting that one enzyme molecule may exercise both, the maintenance and de novo activities. Modification of these methyl accepting polymers with (+/-)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, anti (BPDE) interferes with the methylation reaction, and this inhibition is proportional to the degree of BPDE-modification. This indicates that BPDE - DNA adducts affect both the maintenance and the de novo DNA methyltransferase activities. The mechanism responsible for such inhibition is related neither to interference of BPDE - DNA adducts with the initial binding of the enzyme to DNA nor with the processive mode of action of the enzyme on the modified DNA template. More likely, the BPDE - DNA adducts inhibit the transmethylation reaction directly at the sites of modification.