The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis.
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.
Boiteux
S
S
CEA, DSV, Département de Radiobiologie et Radiopathologie, UMR217 CNRS-CEA Radiobiologie Moléculaire et Cellulaire, Fontenay aux Roses, 92265, France. boiteux@dsvidf.cea.fr
Radicella
J P
JP
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D001483:Base Sequence; D004260:DNA Repair / Q000235:genetics; D043382:DNA-Formamidopyrimidine Glycosylase; D029968:Escherichia coli Proteins; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*
D029968:Escherichia coli Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli