Excision repair of 8-hydroxyguanine in mammalian cells: the mouse Ogg1 protein as a model.
8-Hydroxyguanine (8-OH-Gua) is a major mutagenic lesion produced on DNA by the oxidative stress induced by either the endogen metabolism or the exposure to external agents. In bacteria and yeast this modified base can be removed by specific DNA glycosylases. Recently a human gene coding for an 8-OH-Gua DNA glycosylase/AP lyase has been identified by its homology to the yeast OGG1. This gene is located in human chromosome 3p25, a region commonly rearranged in various cancers, specially in lung tumor cells. We report here the cloning, by sequence homology to the yeast OGG1, of a mouse cDNA coding for a 8-OH-Gua DNA glycosylase with 84% and 38% identity to the human and yeast relevant proteins, respectively. The Ogg1 gene is localized to the mouse chromosome 6E. The mouse Qgg1 cDNA, when expressed in Eschierichia coli, is capable of suppressing the spontaneous mutator phenotype of a DNA repair deficient fpg mutgamma strain. The mouse Ogg1 protein acts efficiently on duplexes in which the 8-OH-Gua is paired with a cytosine but is inactive on 8-OH-Gua: Ade pair, consistently with its proposed biological role in the avoidance of mutations. A comparison of the mouse enzyme with other eukaryotic Ogg1 enzymes is also presented. The isolation of this gene will allow the development of an animal model to study the effects of oxidative stress on carcinogenesis and degenerative diseases.
Boiteux
S
S
CEA/DSV, Département de Radiobiologie et Radiopathologie, UMR217 CNRS/CEA Radiobiologie Moléculaire et Cellulaire, Fontenay-aux-Roses, France. boiteux@dsvidf.cea.fr
Dhérin
C
C
Reille
F
F
Apiou
F
F
Dutrillaux
B
B
Radicella
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins; D005656:Fungal Proteins / Q000235:genetics; D005816:Genetic Complementation Test; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000235:genetics* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015003:Yeasts / Q000235:genetics
D029968:Escherichia coli Proteins; D005656:Fungal Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli