of work: Based upon our previous finding that there is an increase with age in the activity of a mitochondrial DNA glycosylase/endonuclease (mtODE) which is specific for 8-OH deoxyguanosine (8-OHdG), we have hypothesized that there is an induction of this enzyme of DNA repair in response to chronic oxidative stress. In liver mitochondrial extracts from rats,there was a highly significant increase in activity between 6 months and 23 months of age, with the activity being at a maximum at an intermediate age (12 months). The same pattern was seen in extracts of heart mitochondria. By contrast, two other mitochondrial enzymes of DNA metabolism which are not specifically involved in the repair of oxidative damage, viz. uracil DNA glycosylase (mtUDG) and AP endonuclease, were found to be either unchanged or minimally changed with aging. This increase in mitochondrial DNA repair with aging is also seen in mice of different ages. It is surprising and may stimulate new directions as it was previously thought that DNA repair capacity declined with age. Recent experiments have used primary cultures of hepatocytes from young and old rats. We have developed new techniques to measure DNA repair in mitochondria. Using cell extracts, incision and incorporation of damaged DNA can be detected, and we can thus now approach the studies on the changes with aging more mechanistically. Repair of oxidative DNA damage is carried out by the base excision repair system. It has two pathways, long and short patch repair. Using patch size measurements we find that in human cells, oxidative lesions like uracil in DNA is repaired solely by the short patch pathway in mitochondria, while the long patch pathway is extensively used in the nuclear base excision repair.
| Scheibye-Knudsen, Morten; Croteau, Deborah L; Bohr, Vilhelm A (2013) Mitochondrial deficiency in Cockayne syndrome. Mech Ageing Dev 134:275-83 |
| Ramamoorthy, Mahesh; Sykora, Peter; Scheibye-Knudsen, Morten et al. (2012) Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype. Free Radic Biol Med 53:1371-80 |
| Venø, Susanne T; Kulikowicz, Tomasz; Pestana, Cezar et al. (2011) The human Suv3 helicase interacts with replication protein A and flap endonuclease 1 in the nucleus. Biochem J 440:293-300 |
| Gredilla, Ricardo; Garm, Christian; Holm, Rikke et al. (2010) Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging 31:993-1002 |
| Canugovi, Chandrika; Maynard, Scott; Bayne, Anne-Cécile V et al. (2010) The mitochondrial transcription factor A functions in mitochondrial base excision repair. DNA Repair (Amst) 9:1080-9 |
| de Souza-Pinto, Nadja C; Maynard, Scott; Hashiguchi, Kazunari et al. (2009) The recombination protein RAD52 cooperates with the excision repair protein OGG1 for the repair of oxidative lesions in mammalian cells. Mol Cell Biol 29:4441-54 |
| Maynard, Scott; Schurman, Shepherd H; Harboe, Charlotte et al. (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2-10 |
| de Souza-Pinto, Nadja C; Wilson 3rd, David M; Stevnsner, Tinna V et al. (2008) Mitochondrial DNA, base excision repair and neurodegeneration. DNA Repair (Amst) 7:1098-109 |
| Bohr, V A; Ottersen, O P; Tonjum, T (2007) Genome instability and DNA repair in brain, ageing and neurological disease. Neuroscience 145:1183-6 |
| Weissman, L; de Souza-Pinto, N C; Stevnsner, T et al. (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318-29 |
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