The oxidative DNA damage and germline mutation

Abstract

It is well known that reactive oxygen species (ROS) are generated in the cells by radiation and ROS induced cellular damage is a major cause of the indirect effect of radiation. We are focused on the oxidation of nucleic acid to understand the cause of genetic instability. We have suggested that 8-oxoguanine (8-oxoG, major oxidized form of guanine) causes base substitution and chromosome recombination in the mammalian genome. To elucidate the influence of 8-oxoG on germline mutations, we analyzed the expression of each gene (Ogg1, Mth1, Mutyh) in germ cells and the effects of their deficiency. We found that each gene was highly expressed in meiotic cells of the testis. We also observed some cytogenetic abnormalities of chromosomes in the mutant cells. Moreover, triple-mutant mice lacking Ogg1, Mth1 and Mutyh exhibited increased frequency of hereditary congenital abnormalities as well as cancers, suggesting that the accumulation of 8-oxoG in germ cells increases their mutation frequency, thereby generating germline mutations.