8-Hydroxyguanine, DNA Adduct Formed by Oxygen Radicals

Abstract

8-Hydroxyguanine (7,8-dihydro-8-oxoguanine, abbreviated as 8-OH-G or 8-oxo-G) was discovered in 1983 during the course of study to isolate mutagens/carcinogens present in broiled foods. 8-OH-G was produced in DNA by various oxygen radical forming agents not only in in vitro reaction, but in in vivo systems. 8-OH-G became a very important modified base, because it in DNA induces G to T transvertion. Since oxidative DNA damage is a common type of genomic damage, 8-OH-G may play a critical role in a broad range of pathophysiological process, such as carcinogenesis, aging and degenerative diseases. Studies by many investigators in late 1980 to early 1990 showed that the three genes, MutM (a glycosylase/AP-lyase), MutY (a monofunctional DNA glycosylase that cleaves the misincorporated A residue paired with 8-OH-G) and MutT (8-OH-dGTPase which hydrolyzed 8-OH-dGTP in nucleotide pool) are involved in repair of 8-OH-G in E. coli, indicating importance of 8-OH-G in living organisms. An important question raised is whether similar systems for 8-OH-G exist in mammalian cells. In the case of mutY and mutT, similar genes have been identified. On the contrary, mammalian mutM homologues have not been characterized until recently. In June, 1997, six groups independently obtained a human or mouse homologue of yeast Oggl MutM homologue). A single gene in human cells hMMH or hOGGl) produces four isoforms (type Ia, Ib, Ic and II) by alternative splicing. Type 1a expressed in E. coli showed both glycosylase and lyase activity. The isoform, type 1a contained a nuclear localization signal, but others did not, indicating that type 1a is involved in repair of 8-OH-G in nuclear DNA, and others in mitochondrial DNA repair. Whether hMMH is relevant to incidence of certain type of human cancer is an important question answered in future study