Abstract
Reactive oxygen species, produced by cellular metabolisms and by exposure to ionizing radiation or ultraviolet-light, attack DNA and its precursor nucleotides. Consequently, various modified bases are introduced into the DNA of normally growing cells. One such modified base, 8-oxo-7, 8-dihydroguanine (8-oxoG) is highly mutagenic; 8-oxoG can pair with adenine as well as cytosine, causing G:C to T:A transversion during DNA replication. 8-Oxo-dGTP can be incorporated opposite adenine or cytosine in the template strand, thus inducing both A:T to C:G and G:C to T:A transversions. Mammals have three enzymes to prevent the 8-oxoG-related mutagenesis. OGG1 removes 8-oxoG paired with cytosine, and MUTYH excises adenine incorporated opposite 8-oxoG. MTH1 hydrolyses 8-oxo-dGTP, thus avoiding the incorporation of 8-oxo-dGTP into DNA. We generated mutant mice lacking each of these three enzymes by gene targeting, and analyzed mutagenesis and tumorigenesis in these animals. Our data indicate the significance of these enzymes in the prevention of mutagenesis and tumorigenesis. Recently, we developed a new system using the cells derived from the rpsL transgenic mouse, and analyzed the mutagenesis caused by 8-oxo-dGTP. The introduction of 8-oxo-dGTP into the cells drastically induced A:T to C:G transversions but not G:C to T:A transversions. These results suggest that the mutations caused by the incorporated 8-oxoG opposite cytosine were efficiently suppressed by DNA repair systems, while the incorporated 8-oxoG opposite adenine were poorly processed in mammalian cells.
