Abstract
DNA and its precursor nucleotides are constantly oxidized by reactive oxygen species produced through the exposure of ionizing radiation and various types of chemicals in the environment as well as through normal metabolic processes in the cells. The resulting oxidative lesions in DNA and nucleotides are considered to be a major source of spontaneous mutations in many organisms. 8-Oxo-dGTP, an oxidized form of dGTP, can be incorporated into a position opposite of adenine as well as of cytosine during DNA replication. Thus, 8-oxoguanine incorporated with adenine can form a pair with cytosine in the next round of DNA replication, leading to an A:T to C:G transversion; 8-oxoguanine incorporated with cytosine can form a pair with adenine during DNA replication, leading to a G:C to T:A transversion after two round of DNA replication. Organisms are equipped with mechanisms to avoid the mutagenesis caused by the oxidized nucleotides. Bacterial MutT protein hydrolyzes 8-oxo-dGTP and 8-oxo-dGDP to 8-oxo-dGMP, thus preventing the incorporation of the mutagenic substrate during DNA replication. In mammals, proteins belonging to the NUDIX hydrolase family have similar enzymatic activities: MTH1 (NUDT1) and NUDT15 hydrolyze 8-oxo-dGTP while NUDT5 hydrolyzes 8-oxo-dGDP. Thus, these enzymes are considered to function in the preventive mechanisms for mutatgenesis caused by 8-oxo-dGTP. Here we show the data obtained from the mutagenesis and tumorigenesis experiments using Mth1-deficient mice, and discuss mechanisms for preventing mutagenesis caused by oxidized nucleotides in mammals.
