Reactive oxygen species (ROS) are produced through normal cellular metabolism, and their formation is further enhanced by exposure to ionizing radiation and various chemicals. ROS attack
DNA, and the resulting oxidative DNA damage is considered to contribute to aging,
carcinogenesis and neurodegeneration. Among various types of oxidative DNA damage,
8-oxo-7,8-dihydroguanine (8-oxoguanine or 8-oxoG) is the most abundant, and plays significant roles in mutagenesis because of its ability to pair with
adenine as well as
cytosine. Enzymatic activities that may be responsible for preventing 8-oxoG-evoked mutations were identified in mammalian cells. We have focused on the following three
enzymes: MTH1, OGG1 and MUTYH. MTH1 is a mammalian ortholog of Escherichia coli MutT, which hydrolyzes
8-oxo-dGTP to its monophosphate form in
nucleotide pools, thereby preventing incorporation of the mutagenic substrate into
DNA. OGG1, a functional counterpart of E. coli MutM, has an 8-oxoG
DNA glycosylase activity. MUTYH, a mammalian ortholog of E. coli MutY, excises an
adenine paired with 8-oxoG. These three
enzymes are thought to prevent mutagenesis caused by 8-oxoG in mammals. To analyze the functions of mammalian MTH1 (Mth1), OGG1 (Ogg1) and MUTYH (Mutyh) in vivo, we established mutant mice for these three
enzymes by targeted mutagenesis, and investigated spontaneous
tumorigenesis as well as mutagenesis. Here we discuss our recent investigation of mutagenesis and
carcinogenesis in these mutant mice.