Oxidative stress-induced tumorigenesis in the small intestine of various types of DNA repair-deficient mice

Reactive oxygen species attack DNA and its precursor nucleotides, and consequently bases with a various modification are introduced in DNA within normally growing cells. One of such modified bases, 8-oxo-7, 8-dihydroguanine (8-oxoG) is highly mutagenic. Three enzymes, MTH1, OGG1, and MUTYH, play important roles in avoiding the 8-oxoG-related mutagenesis in mammalian cells. We have established an experimental system for oxidative DNA damage-induced mutagenesis and tumorigenesis in the gastrointestinal tracts of mice. Oral administration of KBrO₃ effectively induced G:C to T:A transversions and epithelial tumors in the small intestines of Mutyh-deficient mice, indicating the significance of Mutyh in the suppression of mutagenesis and tumorigenesis induced by KBrO₃. To elucidate the roles of other DNA repair genes in the tumor-suppression, we performed KBrO₃-induced tumorigenesis experiments using Ogg1-, Mth1-, Msh2- and Xpa-deficient mice. We observed an enhanced tumor-formation in the small intestines of Msh2-deficient, but not Xpa-deficient mice. Interestingly, the number of tumors marginally increased in either Ogg1- or Mth1-deficient mice, in contrast to Mutyh-deficient mice. Based on these findings, we will discuss the roles of these DNA repair-related factors in the suppression of oxidative DNA damage-induced mutagenesis and tumorigenesis in the gastrointestinal tracts.