Kohno T, Shinmura K, Tosaka M, Tani M, Kim S R, Sugimura H, Nohmi T, Kasai H, Yokota J
Biology Division, National Cancer Center Research Institute, Tokyo, Japan.
Oncogene. 1998 Jun 25;16(25):3219-25. doi: 10.1038/sj.onc.1201872.
The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh8Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser326 and hOGG1-Cys326 proteins were produced in human cells. Activity in the repair of oh8Gua was greater in hOGG1-Ser326 protein than in hOGG1-Cys326 protein in the complementation assay of an E. coli mutant defective in the repair of oh8Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh8Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh8Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.
hOGG1基因编码一种DNA糖基化酶，可从受损DNA中切除8-羟基鸟嘌呤（oh8Gua）。在正常细胞和肺癌细胞中对hOGG1基因及其转录本进行了结构分析。由于密码子326处的基因多态性，人类细胞中产生了hOGG1-Ser326和hOGG1-Cys326蛋白。在oh8Gua修复存在缺陷的大肠杆菌突变体的互补试验中，hOGG1-Ser326蛋白对oh8Gua的修复活性高于hOGG1-Cys326蛋白。通过可变剪接产生的两种hOGG1转录本异构体编码不同的hOGG1蛋白：一种带有假定的核定位信号，另一种没有。在肺癌细胞中经常检测到hOGG1基因座的杂合性缺失（15/23，62.2%），并且细胞系NCI-H526发生了突变，导致形成编码截短hOGG1蛋白的转录本。然而，无论表达的hOGG1蛋白类型如何，肺癌细胞和白细胞中核DNA的oh8Gua水平相似。这些结果表明，尽管由于hOGG1基因的遗传多态性、突变和可变剪接产生了多种hOGG1蛋白，但oh8Gua水平仍维持在稳定水平。
