Similarities in sunlight-induced mutational spectra of CpG-methylated transgenes and the p53 gene in skin cancer point to an important role of 5-methylcytosine residues in solar UV mutagenesis

In the p53 gene of human sunlight-associated skin cancers, of the mutations involve trinucleotide sequences with the rare base 5-methylcytosine (5'Pym CG). In order to determine the involvement of 5-methylcytosine in sunlight- induced mutations, we have analyzed the cII transgene in mouse cells, a mut ational target gene that we found is methylated at most CpG sequences. We r eport that the mutational spec tra produced by irradiation with 254 nm WC r adiation and simulated sunlight, respectively, differ most dramatically by the much higher involvement of dipyrimidine structures containing 5-methylc ytosine in the solar UV mutation spectrum (32 % versus 9 % of all mutations ). A distinct mutational hotpsot induced by simulated sunlight occurs at a sequence 5'TmCG and is associated with high levels of cis-syn cyclobutane p yrimidine dimer formation. A comparison of sunlight-induced mutational spec tra of the cII and lad transgenes, as well as the p53 gene in skin tumors, shows that 5-methylcytosine is involved in 25 to 40 % of all mutations in a ll three systems. The combined data make a strong case that cyclobutane pyr imidine dimers forming preferentially at dipyrimidine sequences with Ei-met hylcytosine are responsible for a considerable fraction of the mutations in duced by sunlight in mammalian cells. (C) 2001 Academic Press.