Mutagenesis at Methylated CpG Sequences

Abstract

5-Methylcytosine in DNA is genetically unstable. Methylated CpG (mCpG) sequences frequently undergo mutation resulting in a general depletion of this dinucleotide sequence in mammalian genomes. In human genetic disease- and cancerrelevant genes, mCpG sequences are mutational hotspots. It is an almost universally accepted dogma that these mutations are caused by random deamination of 5-methylcytosines. However, it is plausible that mCpG transitions are not caused simply by spontaneous deamination of 5-methylcytosine in double-stranded DNA but by other processes including, for example, mCpG-specific base modification by endogenous or exogenous mutagens or, alternatively, by secondary factors operating at mCpG sequences and promoting deamination. We also discuss that mCpG sequences are favored targets for specific exogenous mutagens and carcinogens. When adjacent to another pyrimidine, 5-methylcytosine preferentially undergoes sunlight-induced pyrimidine dimer formation. Certain polycyclic aromatic hydrocarbons form guanine adducts and induce G to T transversion mutations with high selectivity at mCpG sequences.