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Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1−/− mice

Oncogene volume 25, pages 2425–2432 (2006)Cite this article

Abstract

OGG1 (8-oxoguanine DNA glycosylase-1) is one of the main DNA glycosylases present in mammalian cells. The enzyme removes 7,8-dihydro-8-oxoguanine (8-oxoG) lesions, believed to be the most important oxidized lesions due to their relatively high incidence and their miscoding properties. This study shows that in prenatal mice brains the repair capacity for 8-oxoG is 5–10-fold higher than in adult mice brains. Western blot analysis and repair activity in extracts from Ogg1−/− mice revealed that OGG1 was responsible for the efficient 8-oxoG removal from prenatal mice. To investigate how OGG1 protects against oxidative stress-induced mutagenesis, pregnant Big Blue/wild-type and Big Blue/Ogg1−/− mice were exposed to nontoxic doses of gamma radiation. A 2.5-fold increase in the mutation frequency in Ogg1−/− mouse brains was obtained by exposure to 3.5 Gy at day 19 postfertilization. This was largely due to GC to TA transversions, believed to originate from 8-oxoG mispairing with A during replication. Furthermore, rapid cell divisions seemed to be required for fixation of mutations, as a similar dose of radiation did not increase the mutation frequency, or the frequency of GC to TA transversion, in the adult brain.

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Acknowledgements

This work was supported by the Norwegian Cancer Society and the Research Council of Norway. We are grateful to our group members and to Veslemøy Rolseth and Pål Falnes for critiquing the manuscript. We are also grateful to Einar Rødland for undertaking a statistical analysis of the mutation frequencies.

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Authors and Affiliations

  1. Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, The National Hospital, University of Oslo, Oslo, Norway

    E Larsen, K Reite, G Nesse, C Gran & E Seeberg

  2. Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway

    A Klungland

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  1. E Larsen
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  4. C Gran
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Correspondence to E Larsen.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Larsen, E., Reite, K., Nesse, G. et al. Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1−/− mice. Oncogene 25, 2425–2432 (2006). https://doi.org/10.1038/sj.onc.1209284

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