Genomes and their precursor
nucleotides are highly exposed to
reactive oxygen species, which are generated both as byproducts of
oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in
nucleic acids, mammalian cells are equipped with three distinct
enzymes. MTH1
protein hydrolyzes oxidized
purine nucleoside triphosphates, such as
8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine
triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous
carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A:T-->C:G and G:C-->T:A transversion mutations.
8-Oxoguanine (8-oxoG)
DNA glycosylase, encoded by the OGG1 gene, and
adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G:C to T:A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these
enzymes leads to increased
tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G:C to T:A transversions through the misincorporation of
2-OH-dATP, especially in the intestinal tract, since MUTYH can excise
2-hydroxyadenine opposite
guanine in genomic
DNA and the repair activity is selectively impaired by a mutation found in patients with
autosomal recessive colorectal adenomatous polyposis.