ABSTRACT

Oxidative damage to DNA constitutes a major portion of the endogenous DNA damage in a cell. Most of the oxidative lesions are the result of reactive oxygen species (ROS) interacting with DNA bases and the deoxyribose moiety (1,2). Reactive oxygen species, in particular superoxide radicals, are generated in mitochondria as a result of incomplete reduction of oxygen during oxidative phosphorylation (3). Superoxide is then converted to other forms of ROS including hydrogen peroxide and hydroxyl radicals (Fig. 1) (1,4,5). Reactive oxygen species are also generated when cells are exposed to exogenous agents such as redox chemicals (6), UV [in particular high doses of UVA (7)] radiation, and ionizing radiation (1,2). Singlet oxygen, another highly ROS, is generated via photoreactions in the presence of photoactive pigments or dyes (8,9). The majority of oxidative DNA damage is the result of hydroxyl radicals’ attack on DNA; under physiological condition, hydroxyl radical reacts with DNA at almost diffusion-controlled rates (109M1 sec1-1010M1

sec1) (1,2). Reactions of hydroxyl radicals with DNA bases generate a wide spectrum of

DNA base modifications. The major stable base oxidation products are the hydroxylation products of the 5, 6 double bond of pyrimidines and the C-8 hydroxylation products of purines (1,2). The initial hydroxyl radical adducts of purine and pyrimidines can further react and lead to the formation of ring saturation, contraction, or fragmentation of DNA bases. Figs. 2 and 3 list the structures of a number of commonly identifiable DNA base lesions. Oxidation of DNA bases also leads to increased instability of the N-glycosidic bond and to the formation of apurinic/ apyrimidinic (AP) sites in DNA. However, AP sites are generated predominantly as a result of hydroxyl radical interaction with the deoxyribose moiety (1,2), abstraction of hydrogen, or the addition of hydroxyl radical to the deoxyribose ring, leading to the formation of various kinds of modification of the deoxyribose moiety (1,2). Many of the damaged deoxyribose species are characterized by substantial decrease in the stability the N-glycosidic bond, thus generating various forms of oxidized AP site and DNA-strand breaks containing modified sugar residues or phosphoryl termini (1,2).