Abstract
Oxygen radicals produced by ionizing radiation cause a variety of oxidative damage into DNA and its precursors. Among such damages, 7, 8-dihydro-8-oxoguanine (8-oxoG) is known to be abundant and highly mutagenic. 8-OxoG can pair with adenine as well as cytosine, thus causing G:C to T:A and A:T to C:G tansversions, if not repaired. Enzymes that may prevent 8-oxoG-evoked mutagenesis were identified in mammalian cells. Mth1 hydrolyzes 8-oxo-dGTP, 2-OH-dATP and 8-oxo-dATP to their monophosphate forms in the nucleotide pool, thereby preventing occurrence of mutations caused by oxidation. Ogg1 is an 8-oxoG DNA glycosylase and prevents G:C to T:A tansversion by excising 8-oxoG from 8-oxoG:C pairs. Previously, we analyzed X-ray induced mutagenesis in mice and found a significant increase of A:T to G:C transitions in spleens of Mth1-deficient mice, probably caused by a failure to remove 8-oxo-dATP formed in the nucleotide pools. On the other hand, G:C to T:A tansversion caused by 8-oxo-dGTP did not increase in the animals. These results suggested that Ogg1 might prevent an occurrence of this type of mutation. To examine this possibility, we investigated X-ray induced mutagenesis in Ogg1-deficient mice. Ogg1-/- mice were irradiated with 4 Gy of X-rays at the age of 6 weeks. Two weeks after irradiation, we analyzed mutations in spleens of Ogg1-/- mice and found an increase of G:C to T:A tansversions. These results suggest that Ogg1 could play an important role in preventing the mutagenesis induced by ionizing radiation.
