Nucleotide Excision Repair Defect Influences Lethality and Mutagenicity Induced

Modification of DNA at the 3-position of purines is thought to be a potent block of DNA replication due to the loss of a required contact between this position and an arginine residue that is faithfully conserved in all known DNA polymerases. For this reason we have designed a molecule, Me-lex, that methylates DNA to selectively and efficiently afford 3-MeA. As predicted, Me-lex is cytotoxic at micromolar concentrations in Escherichia coli and in human cells, and cells that are defective in base excision repair (BER) show enhanced sensitivity. The compound causes cell cycle arrest in S-phase, sister chromatid exchange, p53 induction, and apoptosis in Aag null ES cells that cannot remove the lesion from the genome. Because 3-MeA should block DNA replication, which would induce cytotoxicity, it was assumed that Me-lex would not be particularly mutagenic.

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