Oxidative nucleotide damage: consequences and prevention
Oxidative nucleotide damage: consequences and prevention
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DOI：
10.1038/sj.onc.1206023
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发表时间：
2002-12-16
期刊：
影响因子：
8
通讯作者：
Tsuzuki, T
中科院分区：
文献类型：
--
作者：
Sekiguchi, M;Tsuzuki, T
8-氧代鸟嘌呤（8-氧代-7，8-二氢鸟嘌呤）是由细胞代谢过程中通常形成的活性氧在DNA和细胞的核苷酸库中产生的。8-氧代鸟嘌呤核苷酸可以与胞嘧啶和腺嘌呤核苷酸以几乎相同的效率配对，然后发生颠换突变。大肠杆菌的MutT蛋白和相关的哺乳动物蛋白MTH 1特异性地将8-oxo-dGTP降解为8-oxo-dGMP，从而防止8-oxoguanine错误掺入DNA。细菌和哺乳动物的酶在它们的大小上接近，并且共享由23个残基和14个相同氨基酸组成的高度保守区域。在该区域的饱和诱变后，这些残基中的大多数被证明是发挥8-氧代-dGT酶活性所必需的。进行基因靶向以建立MTH 1缺陷细胞系和小鼠用于研究。当出生后18个月进行检查时，与野生型小鼠相比，MTHI-/-小鼠的肺、肝和胃中形成了更多的肿瘤。这些蛋白质保护遗传信息免受内源性氧威胁的不利影响。
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 8oxoguanine 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 MTHI-/- mice, as compared with findings in wild-type mice. These proteins protect genetic information from untoward effects of threats of endogenous oxygen.