Microsatellite instability induced, by hydrogen peroxide in Escherichia coli

Damage to DNA by reactive oxygen species may be a significant source of end ogenous mutagenesis in aerobic organisms. Using a selective assay for micro satellite instability in E. call, we have asked whether endogenous oxidativ e mutagenesis can contribute to genetic instability. Instability of repetit ive sequences, both in intronic sequences and within coding regions, is a h allmark of genetic instability in human cancers. We demonstrate that exposu re of E. coli to low levels of hydrogen peroxide increases the frequency of expansions and deletions within dinucleotide repetitive sequences. Sequenc ing of the repetitive sequences and flanking non-repetitive regions in muta nt clones demonstrated the high specificity for alterations with the repeat s. All of the 183 mutants sequenced displayed frameshift alterations within the microsatellite repeats, and no base substitutions or frameshift mutati ons occurred within the flanking non-repetitive sequences. We hypothesize t hat endogenous oxidative damage to DNA can increase the frequency of strand slippage intermediates occurring during DNA replication or repair synthesi s, and contribute to genomic instability. (C) 2000 Elsevier Science B.V. Al l rights reserved.