Spontaneous tumorigenesis and mutagenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase

• Published in: International Congress series 2002-07, Vol.1236, p.111-114
• Main Authors: Tsuzuki, Teruhisa, Egashira, Akinori, Yamauchi, Kazumi, Yoshiyama, Kaoru, Maki, Hisaji
• Format: Article
• Language: English
• Subjects: 8-Oxoguanine; Gene targeting; Nucleotide sanitization; Oxidative DNA damage; Spontaneous mutation
• ISSN: 0531-5131; 1873-6157
• DOI: 10.1016/S0531-5131(01)00760-9

Oxygen radicals, which can be produced through normal cellular metabolism as well as X-ray irradiation, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity. The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of mutations. When examined 18 months after birth, a greater number of tumors had formed in the lungs, livers and stomachs of MTH1-deficient mice, as compared with wild-type mice. Next, we analysed the mutation frequency and their spectra in each MTH1-deficient or proficient mice at the age of 4 and 24 weeks. The mutation frequency on the rpsL transgene in the spleen samples was determined. However, the spontaneous mutation frequency observed in the spleen samples from the MTH1 −/− mice showed no apparent increase compared to the value of the one in the MTH1 +/+ mice. Furthermore, the site distribution of the mutations that occurred on the rpsL gene was slightly different between these two MTH1 genotypes.