Oxidative nucleotide damage: consequences and prevention.
8-Oxoguanine (8-oxo-7,8-dihydroguanine) is produced in DNA, as well as in nucleotide pools of cells, by reactive oxygen species normally formed during cellular metabolic processes. 8-Oxoguanine nucleotide can pair with cytosine and adenine nucleotides with an almost equal efficiency, then transversion mutation ensues. MutT protein of Escherichia coli and related mammalian protein MTH1 specifically degrade 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing misincorporation of 8-oxoguanine into DNA. The bacterial and mammalian enzymes are close in their size and share a highly conserved region consisting of 23 residues with 14 identical amino acids. Following saturation mutagenesis of this region, most of these residues proved to be essential to exert 8-oxo-dGTPase activity. Gene targeting was done to establish MTH1-deficient cell lines and mice for study. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1(-/-) mice, as compared with findings in wild-type mice. These proteins protect genetic information from untoward effects of threats of endogenous oxygen.
Sekiguchi
Mutsuo
M
Biomolecular Engineering Research Institute, Suita, Osaka 565-0874, Japan. sekiguch@beri.or.jp
Tsuzuki
Teruhisa
T
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004269:DNA, Bacterial / Q000096:biosynthesis; D029968:Escherichia coli Proteins; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D008322:Mammals; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid
D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D005656:Fungal Proteins; C118806:MTH1 protein, S cerevisiae; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D010744:Phosphoric Monoester Hydrolases; D011755:Pyrophosphatases; C052211:mutT protein, E coli