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Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B

Oncogene volume 21, pages 8675–8682 (2002)Cite this article

Abstract

Reactive oxygen species, which are prevalent in mitochondria, cause oxidative DNA damage including the mutagenic DNA lesion 7,8-dihydroxyguanine (8-oxoG). Oxidative damage to mitochondrial DNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. 8-oxoG is repaired efficiently in mammalian mitochondrial DNA by enzymes in the base excision repair pathway, including the 8-oxoguanine glycosylase (OGG1), which incizes the lesion in the first step of repair. Cockayne syndrome (CS) is a segmental premature aging syndrome in humans that has two complementation groups, CSA and CSB. Previous studies showed that CSB-deficient cells have reduced capacity to repair 8-oxoG. This study examines the role of the CSB gene in regulating repair of 8-oxoG in mitochondrial DNA in human and mouse cells. 8-oxoG repair was measured in liver cells from CSB deficient mice and in human CS-B cells carrying expression vectors for wild type or mutant forms of the human CSB gene. For the first time we report that CSB stimulates repair of 8-oxoG in mammalian mitochondrial DNA. Furthermore, evidence is presented to support the hypothesis that wild type CSB regulates expression of OGG1.

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Abbreviations

4-NQO:

4-Nitroquinoline-1-oxide

8-oxoG:

7,8-dihydroxyguanine

AP:

apurinic/apyrimidinic

BER:

base excision repair

CS:

Cockayne Syndrome

CSB:

Cockayne Syndrome group B

Fpg:

formamidopyrimidine DNA glycosylase

FSS:

Fpg sensitive sites

hNTH1:

human homologue of endonuclease III

hX:

hypoxanthine

MB:

Methylene blue

NA-AAF:

N-acetoxy-2-acetylamino-fluorene

MLM:

mouse liver mitochondria

MAG:

3-methyl adenine DNA glycosylase

mt:

mitochondrial

NER:

nucleotide excision repair

OGG1:

8-oxoguanine DNA glycosylase

ROS:

reactive oxygen species

TCR:

transcription coupled repair

Tg:

Thymine glycol

UDG:

uracil DNA glycosylase

UV:

ultraviolet

WCE:

whole cell extract

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Acknowledgements

Tanja Thybo helped prepare the mouse liver mitochondria. Ulla Henriksen and Alfred May provided technical assistance. The project was supported by Danish Research Council, NovoNordic Foundation, The Frænkel Foundation, The Neye Foundation, The Foundation of 17-12-1981, The Netherlands Organization for Scientific Research, and The European Community (QLK6-CT-1999-02002).

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Author notes

  1. Theo G M F Gorgels

    Present address: Netherlands Ophtalmic Research Institute, KNAW Meibergdreef 47, Amsterdam, 1100, BA, The Netherlands

Authors and Affiliations

  1. Department of Molecular Biology, Danish Center for Molecular Gerontology, University of Aarhus, Aarhus C, DK-8000, Denmark

    Tinna Stevnsner & Tina Thorslund

  2. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland, MD, USA

    Simon Nyaga, Nadja C de Souza-Pinto, Barbara A Hogue & Vilhelm A Bohr

  3. Medical Genetics Centre Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Rotterdam, Rotterdam, 3000, DR, The Netherlands

    Gijsbertus T J van der Horst & Theo G M F Gorgels

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Correspondence to Vilhelm A Bohr.

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Stevnsner, T., Nyaga, S., de Souza-Pinto, N. et al. Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B. Oncogene 21, 8675–8682 (2002). https://doi.org/10.1038/sj.onc.1205994

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