Abstract
Oxygen radicals are produced through normal cellular metabolism, and the formation of such radicals is further enhanced by ionizing radiation and by various chemical agents. The oxygen radicals attack DNA and its precursor nucleotides, and consequently induce various oxidized forms of bases in DNA within normally growing cells. The mismatch repair (MMR) system is implicated not only in the correction of replication errors but also in the response to DNA damage to maintain genomic stability. Increasing evidence suggests that MMR is involved in the process of avoiding mutagenesis caused by oxidative DNA damages in mammalian cells. We have recently established an experimental system to study oxidative DNA damage-induced mutagenesis and tumorigenesis in the gastrointestinal tracts of mice. To elucidate the role of MMR in the avoidance of oxidative stress-induced tumorigenesis, we performed KBrO3-induced tumorigenesis experiments using Msh2-deficient mice. Chronic exposure to KBrO3 resulted in multiple tumor formation in the small intestines of Msh2-deficient mice, indicating that MMR is involved in the suppression of oxidative stress-induced intestinal tumorigenesis in mice. We also present data obtained from mutation analysis of the tumor-associated genes such as ctnnb1 (b-catenin), k-ras, Trp53 genes in the intestinal tumors of Msh2-deficient mice treated with KBrO3.
