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 po tentially mutagenic DNA lesions that cause G:C-->A:T and A:T-->G:C tra nsition 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 v ary 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 pre vent 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 viv o respectively, All five MTases give complete protection against G:C-- >A:T transitions, However, while the microbial MTases give complete pr otection against A:T-->G:C transitions, the mammalian MTases actually sensitize cells to A:T-->G:C transitions, We hypothesize that the mamm alian MTases bind (OMeT)-Me-4 lesions in vivo but that, because they a re 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.