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. Stroke is the leading cause of neurological disability and the third biggest killer in the US. During a stroke, patients experience an acute interruption of blood flow to the brain, this leads to reperfusion injury, oxidative damage and cell death. We have recently shown that OGG1 plays a significant role in the recovery following a stroke. Using the OGG1 knockout (KO) mouse model, we evaluated the importance of OGG1 after permanent middle cerebral artery occlusion. We observed larger cortical infarcts areas and behavior deficits in the OGG1 KO mice than in WT mice. Additionally, in vitro, the cortical neurons isolated from OGG1 KO mice were more vulnerable to oxidative insults. Our results suggest that the ability to repair oxidatively generated DNA damage has implications for the vulnerability of neurons to metabolic and oxidative stress, and additionally on the functional outcomes after stroke. 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.
| Fang, Evandro Fei; Froetscher, Lynn; Scheibye-Knudsen, Morten et al. (2018) Emerging antitumor activities of the bitter melon (Momordica charantia). Curr Protein Pept Sci : |
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| 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 23:1093-1112 |
| 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 16:2641-2650 |
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