The OGG1 Gene Encodes a Repair Enzyme for Oxidatively Damaged DNA and Is Involved in Human Carcinogenesis

Abstract

8-Hydroxyguanine (oh⁸G) is a major base lesion produced by reactive oxygen species. oh⁸G in DNA causes G:C to T:A transversions and, thus, could be responsible for mutations that lead to carcinogenesis. A human DNA glycosylase/AP lyase encoded by the OGG1 gene has an activity to remove directly oh⁸G from DNA, and suppresses the mutagenic effect of oh⁸G. OGG1 protein has a helix-hairpin-helix-GPD motif as a domain for both DNA binding and catalysis, a nuclear localization signal, and a mitochondria targeting signal. Among multiple OGG1 isoforms, OGG1-type 1a is expressed predominantly in human cells and repairs chromosomal DNA in the nucleus. Inactivation of the OGG1 gene in yeast and mice leads to elevated spontaneous mutation frequency in the cells. The human OGG1 gene maps to chromosome 3p26.2, and allelic deletions of this region occur frequently in a variety of human cancers. Moreover, the OGG1 gene is somatically mutated in some cancer cells and is highly polymorphic among human populations. Repair activities of some mutated and polymorphic OGG1 proteins are lower than those of wild-type OGG1-type 1a-Ser326 protein and, thus, could be involved in human carcinogenesis.