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

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• 作者：Dharini Shah ; Jack Kelly ; Yi Zhang ; Prasad Dande ; Juan Martinez ; Gretchen Ortiz ; Gilberto Fronza ; Huy Tran ; Ana Maria Soto ; Luis Marky ; and Barry Gold
• 刊名：Biochemistry
• 出版年：2001
• 出版时间：February 13, 2001
• 年：2001
• 卷：40
• 期：6
• 页码：1796 - 1803
• 全文大小：114K
• 年卷期：v.40,no.6(February 13, 2001)
• ISSN：1520-4995

文摘

It has been previously reported that a neutral DNA equilibrium binding agent based on anN-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 lexdipeptide 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 monocationicsulfone compounds bind to DNA with K_b's of 10⁵ in primarily entropy-driven reactions. To determinehow 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 (tagand/or alkA glycosylases or apn endonuclease), nucleotide excision repair (uvrA), and both base andnucleotide excision repair (tag/alkA/uvrA). The results clearly demonstrate the cellular toxicity of theN3-methyladenine lesion, and the protective role of base excision glycosylase proteins. A novel findingis that in the absence of functional base excision glycosylases, nucleotide excision repair can also protectcells from this cytotoxic minor groove lesion. Interaction between base and nucleotide excision repairsystems is also seen in the protection of cells treated with cis-diamminedichloroplatinum(II) but not withanti-(±)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.