Mechanisms of oxidative DNA damage; lesions and their measurement

Free radicals produce a number of lesions in DNA such as base lesions, sugar lesions, single-strand breaks, double-strand breaks, abasic sites and DNA-protein cross-links by a variety of mechanisms. Hydroxyl radical, hydrated electron and H atom react with the heterocyclic bases in DNA by addition. In oxygenated systems, adduct radicals of pyrimidines are converted into corresponding peroxyl radicals with oxygen. Hydroxyl radical reacts with purines at diffusion-controlled rates by addition to C4-, C5- and C8-positions. A fraction of hydroxyl radicals reacts with the sugar moiety in DNA by abstraction of H atoms from all five carbon atoms, producing sugar radicals. Further reactions of DNA radicals result in formation of numerous products. The types and yields of DNA modifications profoundly depend on the free radical-generating system, experimental conditions, and the presence or absence of oxygen. In chromatin, DNA-protein cross-links are formed by combination of two radicals, or by radical addition reactions. A number of analytical techniques have been used to identify and quantify a variety of products of DNA. Many pyrimidine and purine lesions have been identified and quantified in cells and tissues. Evidence indicates that most products arise as a result of reactions of hydroxyl radical with DNA constituents in cells. A number of DNA lesions possess premutagenic properties. The biological consequences of DNA modifications in cells are largely unknown and await further exploration.