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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Fang, Evandro Fei; Scheibye-Knudsen, Morten; Chua, Katrin F et al. (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308-21
Cheng, Aiwu; Yang, Ying; Zhou, Ye et al. (2016) Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. Cell Metab 23:128-42
Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten et al. (2016) Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab 23:1093-112
Nygaard, Rie Harboe; Maynard, Scott; Schjerling, Peter et al. (2016) Acquired Localized Cutis Laxa due to Increased Elastin Turnover. Case Rep Dermatol 8:42-51
Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2016) Genome instability in Alzheimer disease. Mech Ageing Dev :
Van Meter, Michael; Simon, Matthew; Tombline, Gregory et al. (2016) JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep 16:2641-50
Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo et al. (2015) Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice. Am J Respir Cell Mol Biol 52:25-36
Ghosh, Somnath; Canugovi, Chandrika; Yoon, Jeong Seon et al. (2015) Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice. Neurobiol Aging 36:2319-30
Bürkle, Alexander; Grune, Tilman; Gonos, Efstathios S et al. (2015) Editorial. Mech Ageing Dev 151:1
Soerensen, Mette; Nygaard, Marianne; Dato, Serena et al. (2015) Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals. Aging Cell 14:60-6

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