Oxidative DNA Damage And Its Processing

National Institute On Aging

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Abstract

Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions. We and others identified several protein interactions for the core BER enzymes. These protein interactions are physical and functional and together support the passing of baton model, in which BER takes place in different steps supported by individual protein interactions that are components of a repair complex, possibly situated at the DNA lesion. Increased levels of oxidative DNA damage is found in cancer cells. Thus we initiated a study to evaluate both mitochondrial and nuclear BER enzyme activity levels between normal and cancerous cells. We noted that OGG1 and NTH1 activities were up-regulated in cancer cell mitochondria but either down-regulated or showed no change in the nuclear fraction, respectively. Our results support the idea that alterations in BER capacity could be associated with carcinogenesis. There are numerous reports in the literature about how foods or food supplements can cause or mitigate damage to DNA. Fruits, like peaches and nectarines, contain many vitamins, fiber and polyphenolic compounds. Therefore, we undertook both a biochemical and microarray study on how peaches and nectarines affect DNA repair BER enzyme activities, in both the nuclear and mitochondrial compartments, and gene expression patterns. We observed that NTH1 was up-regulated and that there was a concomitant decrease in formamidopyrimidines in peach-fed mice. Thus this report supports the idea that diet may be able to modulate DNA repair activities and gene expression patterns. Telomeres are protein-DNA complexes at the ends of chromosomes that protect them from degradation. Telomere shortening has been linked to cellular senescence and human aging. The oxidative theory of aging purposes that oxidative damage accumulates with age and leads to functional decline. We have investigated the consequence of 8-oxodG, a common oxidative DNA base adduct in DNA, in telomeric DNA. We find that telomeric DNA, composed of TTAGGG, is more prone to oxidative damage and repaired less efficiently. Thus, oxidative DNA damage in telomeric DNA may accumulate with age due to poor repair. Future work will evaluate the processing of other oxidative lesions when situated within telomeric DNA.