PMID:14640700
| Citation |
Varadarajan, S, Shah, D, Dande, P, Settles, S, Chen, FX, Fronza, G and Gold, B (2003) DNA damage and cytotoxicity induced by minor groove binding methyl sulfonate esters. Biochemistry 42:14318-27 |
|---|---|
| Abstract |
Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl sulfonate ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mutant strains defective in base excision repair (tag and/or alkA or apn). The results demonstrate the importance of 3-methyladenine, and in some cases 3-methylguanine, lesions in cellular toxicity, and the dominant protective role of the DNA glycosylases. There is no evidence that the sequence specificity is related to toxicity. |
| Links |
PubMed Online version:10.1021/bi0353272 |
| Keywords |
Adenine/analogs & derivatives; Adenine/metabolism; Adenine/toxicity; Anti-Bacterial Agents/toxicity; Base Sequence/drug effects; DNA Adducts/analysis; DNA Adducts/metabolism; DNA Damage; DNA Fragmentation/drug effects; DNA Methylation/drug effects; DNA Repair/drug effects; DNA, Bacterial/drug effects; DNA, Bacterial/metabolism; Escherichia coli/drug effects; Escherichia coli/genetics; Escherichia coli/growth & development; Esters; Guanine/analogs & derivatives; Guanine/metabolism; Guanine/toxicity; Mesylates/toxicity; Molecular Sequence Data; Netropsin/analogs & derivatives; Netropsin/chemical synthesis; Netropsin/chemistry; Netropsin/toxicity; Nucleic Acid Conformation/drug effects; Protein Binding/drug effects |
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