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Carcinogenesis ; 22(9): 1459-63, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11532868

RESUMEN

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.


Asunto(s)
Daño del ADN , Guanina/análogos & derivados , Guanina/metabolismo , N-Glicosil Hidrolasas/deficiencia , Factores de Edad , Animales , División Celular/fisiología , ADN/metabolismo , Reparación del ADN/fisiología , ADN-Formamidopirimidina Glicosilasa , Fibroblastos/citología , Fibroblastos/enzimología , Fibroblastos/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Masculino , Ratones , Ratones Noqueados , N-Glicosil Hidrolasas/genética , N-Glicosil Hidrolasas/metabolismo , Especificidad de Órganos , Estrés Oxidativo/fisiología , Oxígeno/metabolismo
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