A CYTOSINE METHYLTRANSFERASE CONVERTS 5-METHYLCYTOSINE IN DNA TO THYMINE

Sites of cytosine methylation are known to be hot spots for C . G to T . A mutations in a number of systems, including human cells. Traditio nally, spontaneous hydrolytic deamination of 5-methylcytosine to thymi ne has been invoked as the cause of this phenomenon. We show here that a bacterial cytosine methyltransferase can convert 5-methylcytosine i n DNA to thymine and that this reaction creates a mutational hot spot at a site of DNA methylation. The reaction is fairly insensitive to th e methyl donor in the reaction, S-adenosylmethionine. In many cancers, the most frequent class of mutations is C to T changes within CG dinu cleotides of the tumor suppressor gene p53. Because of the similaritie s of the reaction mechanisms of mammalian and bacterial enzymes and th e physiology of the cancer cells, this reaction is expected to contrib ute to mutations at CG dinucleotides in precancerous cells.