Mammalian DNA repair methyltransferases shield (OMeT)-Me-4 from nucleotide excision repair

O-6-Methylguanine (O(6)MeG) and O-4-methylthymine ((OMeT)-Me-4) are potentially mutagenic DNA lesions that cause G:C-->A:T and A:T-->G:C transition mutations by mispairing during DNA replication, and the repair of O(6)MeG and (OMeT)-Me-4 by DNA repair methyltransferases (MTases) is therefore expected to prevent methylation-induced transitions, The efficiency of O(6)MeG and (OMeT)-Me-4 repair by different MTases can vary by several hundred-fold and the aim of this study was to establish the biological consequences of such differences in the efficiency of repair, The ability of three microbial and two mammalian MTases to prevent methylation-induced G:C-->A:T and A:T-->G:C transitions is taken as a measure of their ability to repair O(6)MeG and (OMeT)-Me-4 in vivo respectively, All five MTases give complete protection against G:C-->A:T transitions, However, while the microbial MTases give complete protection against A:T-->G:C transitions, the mammalian MTases actually sensitize cells to A:T-->G:C transitions, We hypothesize that the mammalian MTases bind (OMeT)-Me-4 lesions in vivo but that, because they are extremely slow at subsequent methyl transfer, binding shields (OMeT)-Me-4 from repair by the nucleotide excision repair pathway, Results are presented to support this hypothesis.