Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging

Reactive species generated by chemicals and UV radiation can cause sequence -specific DNA damage and play important roles in mutagenesis, carcinogenesi s and aging. We have investigated sequence specificity of oxidative stress- mediated DNA damage by using P-32-labeled DNA fragments obtained from the h uman c-Ha-ras-1 and p53 genes. Free hydroxyl radical causes DNA damage with no marked site specificity. Reactive nitrogen species, sulfate radicals, n itrogen-centered radicals, benzoyloxyl radical and alkoxyl radical show dif ferent sequence specificity. Benzoyloxyl radical specifically causes damage to the 5'-G in GG sequence. UVA radiation also causes DNA damage at this s ite through electron transfer in the presence of certain photosensitizers. The 5'-G in GG sequence is easily oxidized because a large part of the high est occupied molecular orbital is distributed on this site. On the basis of these findings, the sequence specificity of DNA damage is presumably deter mined by (a) redox potential of reactive species; (b) ionization potential of DNA bases; and (c) site-specific binding of metal ion to DNA. Here we di scuss the mechanisms of sequence-specific DNA damage in relation to carcino genesis and aging. (C) 2001 Elsevier Science B.V. All rights reserved.