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A global DNA repair mechanism involving the Cockayne syndrome B (CSB) gene product can prevent the in vivo accumulation of endogenous oxidative DNA base damage

Oncogene volume 21, pages 8232–8239 (2002)Cite this article

Abstract

The Cockayne syndrome B (CSB) gene product is involved in the repair of various types of base modifications in actively transcribed DNA sequences. To investigate its significance for the repair of endogenous oxidative DNA damage, homozygous csb−/−/ogg1−/− double knockout mice were generated. These combine the deficiency of CSB with that of OGG1, a gene coding for the mammalian repair glycosylase that initiates the base excision repair of 7,8-dihydro-8-oxoguanine (8-oxoG). Compared to ogg1−/− mice, csb−/−/ogg1−/− mice were found to accumulate with age severalfold higher levels of oxidited purine modifications in hepatocytes, splenocytes and kidney cells. In contrast, the basal (steady-state) levels of oxidative DNA modifications in cells from csb−/− mice were not different from those in wild-type mice and did not increase with age. The analysis of the repair rates of additional oxidative DNA base modifications induced by photosensitization in immortalized embryonic fibroblasts was in accordance with these findings: compared to wild-type cells, the global repair was only slightly affected in csb−/− cells, more compromised in ogg1−/− cells, but virtually absent in csb−/−/ogg1−/− cells. An inhibition of transcription by α-amanitin did not block the Csb-dependent repair in ogg1−/− fibroblasts. The influence of Csb on the global repair of 8-oxoG was not detectable in assays with total protein extracts and in a shuttle vector system. The data indicate a role for Csb in the removal of 8-oxoG from the overall genome that is independent of both Ogg1-mediated base excision repair and regular transcription.

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Acknowledgements

We thank Dr Deborah Barnes (Cancer Research UK, London) for providing ogg1−/− mice. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 519), the PROCOPE program and the Association pour la Recherche sur le Cancer (No 5432 to S Boiteux). E Larsen and A Klungland acknowledge the support from the Norwegian Cancer Society, the Top research Program, the Research Council of Norway and support to the ‘DNage’ collaboration by the EU.

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Authors and Affiliations

  1. Institute of Pharmacy, University of Mainz, Mainz, D-55099, Germany

    Marcel Osterod & Bernd Epe

  2. Centre of Molecular Biology and Neuroscience, and Institute of Medical Microbiology, University of Oslo, National Hospital, Oslo, N-0027, Norway

    Elisabeth Larsen & Arne Klungland

  3. Département de Radiobiologie et Radiopathologie, CEA, UMR217 CNRS/CEA, F-92265 Fontenay-aux-Roses, France

    Florence Le Page & Serge Boiteux

  4. Institute of Toxicology, University of Mainz, Mainz, D-55099, Germany

    Jan G Hengstler

  5. Department of Cell Biology and Genetics, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands

    Gijsbertus TJ van der Horst

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  1. Marcel Osterod
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Correspondence to Bernd Epe.

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Osterod, M., Larsen, E., Le Page, F. et al. A global DNA repair mechanism involving the Cockayne syndrome B (CSB) gene product can prevent the in vivo accumulation of endogenous oxidative DNA base damage. Oncogene 21, 8232–8239 (2002). https://doi.org/10.1038/sj.onc.1206027

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