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

D. Shah, J. Kelly, Y. Zhang, P. Dande, J. Martinez, G. Ortiz, G. Fronza, H. Tran, A. M. Soto, L. Marky, B. Gold

Research output: Contribution to journalArticle

Abstract

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-methyladenine lesion, and the protective role of base excision glycosylase proteins. A novel finding is that in the absence of functional base excision glycosylases, nucleotide excision repair can also protect cells from this cytotoxic minor groove lesion. Interaction between base and nucleotide excision repair systems is also seen in the protection of cells treated with cis-diamminedichloroplatinum(II) but not with anti-(±)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyr ene.

Original languageEnglish
Pages (from-to)1796-1803
Number of pages8
JournalBiochemistry
Volume40
Issue number6
DOIs
Publication statusPublished - Feb 13 2001

ASJC Scopus subject areas

  • Biochemistry

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