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Oxidative nucleotide damage: consequences and prevention

Oncogene volume 21, pages 8895–8904 (2002)Cite this article

Abstract

8-Oxoguanine (8-oxo-7,8-dihydroguanine) is produced in DNA, as well as in nucleotide pools of cells, by reactive oxygen species normally formed during cellular metabolic processes. 8-Oxoguanine nucleotide can pair with cytosine and adenine nucleotides with an almost equal efficiency, then transversion mutation ensues. MutT protein of Escherichia coli and related mammalian protein MTH1 specifically degrade 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing misincorporation of 8-oxoguanine into DNA. The bacterial and mammalian enzymes are close in their size and share a highly conserved region consisting of 23 residues with 14 identical amino acids. Following saturation mutagenesis of this region, most of these residues proved to be essential to exert 8-oxo-dGTPase activity. Gene targeting was done to establish MTH1-deficient cell lines and mice for study. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1−/− mice, as compared with findings in wild-type mice. These proteins protect genetic information from untoward effects of threats of endogenous oxygen.

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Acknowledgements

We thank Drs H Hayakawa, H Maki, Y Nakabeppu, Y Yamagata, Y Nakatsu and H Shimokawa for discussion and helpful advice, and M Ohara for useful comments on the manuscript.

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Authors and Affiliations

  1. Biomolecular Engineering Research Institute, Suita, 565-0874, Osaka, Japan

    Mutsuo Sekiguchi

  2. Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Teruhisa Tsuzuki

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Correspondence to Mutsuo Sekiguchi.

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Sekiguchi, M., Tsuzuki, T. Oxidative nucleotide damage: consequences and prevention. Oncogene 21, 8895–8904 (2002). https://doi.org/10.1038/sj.onc.1206023

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