Evidence in Escherichia coli that N3-Methyladenine Lesions Induced by a Minor Groove Binding Methyl Sulfonate Ester Can Be Processed by both Base and Nucleotide Excision Repair†

It has been previously reported that a neutral DNA equilibrium binding agent 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 dipeptide with calf thymus DNA, we have prepared stable, nonmethylating sulfone analogues of MeOSO2-lex that are neutral and cationic. Thermodynamic studies show that both the neutral and monocationic sulfone compounds bind to DNA with Kb's of 105 in primarily entropy-driven reactions. To determine how the cytotoxic N3-methyladenine adduct generated from MeOSO2-lex is repaired 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 glycosylases or apn endonuclease), nucleotide excision repair (uvrA), and both base and nucleotide excision repair (tag/alkA/uvrA). The results clearly demonstrate the cellular toxicity of the N3-methylad...