The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis

Arch Biochem Biophys. 2000 May 1;377(1):1-8. doi: 10.1006/abbi.2000.1773.

Abstract

A particularly important stress for all cells is the one produced by reactive oxygen species (ROS) that are formed as byproducts of cell metabolism. Among DNA damages induced by ROS, 8-hydroxyguanine (8-OH-G) is certainly the product that has retained most of the attention in the past few years. The biological relevance of 8-OH-G in DNA has been unveiled by the study of Escherichia coli and Saccharomyces cerevisiae genes involved in the neutralization of the mutagenic effects of 8-OH-G. These genes, fpg and mutY for E. coli and OGG1 for yeast, code for DNA glycosylases. Inactivation of any of those genes leads to a spontaneous mutator phenotype, characterized by the increase in GC to TA transversions. In yeast, the OGG1 gene encodes a DNA glycosylase/AP lyase that excises 8-OH-G from DNA. In human cells, the OGG1 gene is localized on chromosome 3p25 and encodes two forms of hOgg1 protein which result from an alternative splicing of a single messenger RNA. The alpha-hOgg1 protein has a nuclear localization whereas the beta-hOgg1 is targeted to the mitochondrion. Biochemical studies on the alpha-hOgg1 protein show that it is a DNA glycosylase/AP lyase that excises 8-OH-G and Fapy-G from gamma-irradiated DNA. Several approaches have been used to study the biological role of OGG1 in mammalian cells, ranging from its overexpression in cell lines to the generation of homozygous ogg1-/- null mice. Furthermore, to explore a possible role in the prevention of cancer, the cDNA coding for alpha-hOgg1 has been sequenced in human tumors. All these results point to 8-OH-G as an endogenous source of mutations in eukaryotes and to its likely involvement in the process of carcinogenesis. A review of the recent literature on the mammalian Ogg1 proteins, the main repair system involved in the elimination of this mutagenic lesion, is presented.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Amino Acid Sequence
  • Animals
  • Base Pair Mismatch / genetics
  • Base Sequence
  • DNA Repair / genetics
  • DNA-Formamidopyrimidine Glycosylase
  • Escherichia coli Proteins*
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • N-Glycosyl Hydrolases / chemistry*
  • N-Glycosyl Hydrolases / deficiency
  • N-Glycosyl Hydrolases / genetics
  • N-Glycosyl Hydrolases / metabolism*
  • Neoplasms / genetics*
  • Neoplasms / metabolism*

Substances

  • Escherichia coli Proteins
  • 8-hydroxyguanine
  • Guanine
  • N-Glycosyl Hydrolases
  • DNA-Formamidopyrimidine Glycosylase
  • DNA-formamidopyrimidine glycosylase, E coli