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Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice

Oncogene volume 26, pages 4044–4048 (2007)Cite this article

Abstract

The Cockayne syndrome B protein (CSB) has long been known to be involved in the repair of DNA modifications that block the RNA polymerase in transcribed DNA sequences (transcription-coupled repair). Recent evidence suggests that it also has a more general role in the repair of oxidative DNA base modifications such as 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG). In mammalian cells, 8-oxoG is a substrate of the repair glycosylase OGG1. Mice without this enzyme accumulate 8-oxoG in the genome and have elevated spontaneous mutation rates. To elucidate the role of CSB in the prevention of mutations by oxidative DNA base damage, we have generated mice that are deficient in Csb or Ogg1 or both genes and carry a non-transcribed bacterial lacI gene for mutation analysis (Big Blue mice). Our results indicate that the overall spontaneous mutation frequencies in the livers of Csbm/m/Ogg1−/−-mice are elevated not only compared with heterozygous control mice (factor 3.3), but also with Ogg1−/−-animals (factor 1.6). Sequence analysis revealed that the additional mutations caused by CSB deficiency in an Ogg1−/− background are mostly G:C to T:A transversions and small deletions. For all mouse strains, the background levels of oxidative purine modifications in the livers correlate linearly with the numbers of G:C to T:A transversions observed. The data indicate that CSB is involved in the inhibition of mutations caused by spontaneous oxidative DNA base damage in a non-transcribed gene.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (Ep11/5) and the DAAD. We are grateful to Lydia Weidenfeller and Karin Pauly for excellent technical help and animal care.

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Authors and Affiliations

  1. Institute of Pharmacy, University of Mainz, Mainz, Germany

    C Trapp & B Epe

  2. Center for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet, Oslo, Norway

    K Reite & A Klungland

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  1. C Trapp
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  2. K Reite
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  3. A Klungland
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  4. B Epe
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Correspondence to B Epe.

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

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Trapp, C., Reite, K., Klungland, A. et al. Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice. Oncogene 26, 4044–4048 (2007). https://doi.org/10.1038/sj.onc.1210167

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