INFLUENCE OF OXYGEN RADICAL INJURY ON DNA METHYLATION

One of the most prevalent products of oxygen radical injury in DNA is 8-hydroxyguanosine. Cells must be able to withstand damage by oxygen r adicals and possess specific repair mechanisms that correct this oxida tive lesion. However, when these defenses are oversaturated, such as u nder conditions of high oxidative stress, or when repair is inefficien t, the miscoding potential of this lesion can result in mutations in t he mammalian genome. In addition to causing genetic changes, active ox ygen species can lead to epigenetic alterations in DNA methylation, wi thout changing the DNA base sequence. Such changes in DNA methylation patterns can strongly affect the regulation of expression of many gene s. Although DNA methylation patterns have been found to be altered dur ing carcinogenesis, little is known about the mechanism(s) that produc e this loss of epigenetic controls of gene expression in tumors. Repla cement of guanine with the oxygen radical adduct 8-hydroxyguanine prof oundly alters methylation of adjacent cytosines, suggesting a role for oxidative injury in the formation of aberrant DNA methylation pattern s during carcinogenesis. In this paper, we review both the genetic and epigenetic mechanisms of oxidative DNA damage and its association wit h the carcinogenic process, with special emphasis on the influence of free radical injury on DNA methylation.