hOGG1 Gene Alterations in Human Clear Cell Carcinomas of The Kidney: Effect of Single Mutations in hOGG1 Gene on Substrate Specificity of The hOgg1 Protein

Abstract

Damage to DNA by oxygen free radicals is postulated to cause mutations that are associated to the initiation and/or the progression of human cancers (Breimer, 1990). Oxidative damage-induced mutations can activate oncogenes or inactivate tumor suppressor genes altering the cell growth control (Fearon, 1997). An oxidatively damaged guanine, 7,8-dihydro-8-oxoguanine (8-OxoG) is abundantly produced in DNA as a consequence of the cellular oxidative metabolism, exposure to ionizing radiation or chemical carcinogens. The presence of 8-OxoG in DNA has been shown to be mutagenic since it preferentially pairs to adenine during in vitro DNA synthesis (Shibutani et al., 1991) and generates a mutator phenotype characterized by a high frequency of G:C to T:A transversions (reviewed in Boiteux et al. (Boiteux and Radicella, 2000). In mammalian cells, the OGG1 gene codes for an 8-OxoG DNA glycosylase/AP lyase that has the capacity to excise this oxidized guanine from DNA. Mice lacking a functional Oggl protein accumulate abnormal levels of 8-OxoG in their genomes and display a moderately elevated spontaneous mutation rate in nonproliferative tissues. Since the inactivation of the OGG1 gene in mammalian cells causes a mutator phenotype, it can be expected that cells lacking the Oggl activity could have enhanced probability to undergo cancer transformation (Loeb, 1991). The validation of this hypothesis requires the identification of human tumors where both alleles of the OGG1 are non functional.