title: Age-related and tissue-specific accumulation of oxidative DNA base damage in 7,8-dihydro-8-oxoguanine-DNA glycosylase (Ogg1) deficient mice.
abstract: Mutations that influence the repair of oxidative DNA modifications are expected to increase the steady-state (background) levels of these modifications and thus create a mutator phenotype that predisposes to malignant transformation. We have analysed the steady-state levels and repair kinetics of oxidative DNA modifications in cells of homozygous ogg1(-/-) null mice, which are deficient in Ogg1 protein, a DNA repair glycosylase that removes the miscoding base 8-hydroxyguanine (8-oxoG) from the genome. Oxidative purine modifications including 8-oxoG were quantified by means of an alkaline elution assay in combination with Fpg protein, the bacterial functional analogue of Ogg1 protein. In primary hepatocytes of adult ogg1(-/-) mice aged 9-12 months, the steady-state level of the lesions was 2.8-fold higher than in wild-type control mice. In contrast, no difference between ogg1(-/-) and wild-type mice was observed in splenocytes, spermatocytes and kidney cells. In hepatocytes of ogg1(-/-) mice, but not in wild-type controls, the steady-state levels increased continuously over the whole lifespan. No significant accumulation of the oxidative base modifications was observed in ogg1(-/-) fibroblasts in culture when they were kept confluent for 8 days. Both in confluent and proliferating ogg1(-/-) fibroblasts, the global repair of additional oxidative base modifications induced by photosensitization was 4-fold slower than in wild-type cells. The results suggest that the consequences of an Ogg1 defect are restricted to slowly proliferating tissues with high oxygen metabolism such as liver, because of a back-up mechanism for the repair of 8-oxoG residues that is independent of transcription and replication.
authors.affiliation: Institute of Pharmacy and Institute of Toxicology, University of Mainz, D-55099 Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Osterod
authors.forename: S
authors.initials: S
authors.lastname: Hollenbach
authors.forename: J G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: D E
authors.initials: DE
authors.lastname: Barnes
authors.forename: T
authors.initials: T
authors.lastname: Lindahl
authors.forename: B
authors.initials: B
authors.lastname: Epe
mesh_terms: D000367:Age Factors; D000818:Animals; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D043382:DNA-Formamidopyrimidine Glycosylase; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009699:N-Glycosyl Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D010100:Oxygen