Evidence in Escherichia coli that N3-methyladenine lesions induced by a minor groove binding methyl sulfonate ester can be processed by both base andnucleotide excision repair

It has been previously reported that a neutral DNA equilibrium binding agen t based on an N-methylpyrrolecarboxamide dipeptide (lex) and modified with an O-methyl sulfonate ester functionality (MeOSO2-lex) selectively affords N3-methyladenine lesions. To study the interaction of the neutral lex dipep tide with calf thymus DNA, we have prepared stable, nonmethylating sulfone analogues of MeOSO2-lex that are neutral and cationic. Thermodynamic studie s show that both the neutral and monocationic sulfone compounds bind to DNA with K-b's Of 10(5) ill primarily entropy-driven reactions. To determine h ow the cytotoxic N3-methyladenine adduct generated from MeOSO2-lex is repai red in E. coli, MeOSO2-lex was tested for toxicity in wild-type E. coli and in mutant strains defective in base excision repair (tag and/or alkA glyco sylases or npn endonuclease), nucleotide excision repair (uvrA), and both b ase and nucleotide excision repair (tag/alkA/uvrA). The results clearly dem onstrate the cellular toxicity of the N3-methyladenine lesion, and the prot ective role of base excision glycosylase proteins. A novel finding is that in the absence of functional base excision glycosylases, nucleotide excisio n repair can also protect cells from this cytotoxic minor groove lesion. In teraction between base and nucleotide excision repair systems is also seen in the protection of cells treated with cis-diamminedichloroplatinum(II) bu t not with anti-(+/-)-r-7,t-8-dihydroxy-t-9, 10-epoxy-7,8,9,10-tetrahydrobe nzo[a]pyrene.