Xie Yali, Yang Hanjing, Miller Jeffrey H, Shih Diana M, Hicks Geoffrey G, Xie Jiuyong, Shiu Robert P
Department of Physiology, University of Manitoba, 730 William Avenue, Winnipeg, MB R3E 0W9, Canada.
Carcinogenesis. 2008 Apr;29(4):722-8. doi: 10.1093/carcin/bgn033. Epub 2008 Feb 6.
Oxidative stress generated from endogenous and exogenous sources causes oxidative DNA damage. The most frequent mutagenic base lesion 7,8-dihydro-8-oxoguanine and the resulting mismatched adenine are removed by OGG1 and MYH in mammals. Deficiencies in human MYH or mouse MYH and OGG1 result in tumor predisposition but the underlying molecular mechanism is not fully understood. To facilitate the study of the roles of MYH and OGG1 in the protection against oxidative stress, we generated mouse embryonic fibroblast cell lines deficient in these genes. Myh and Ogg1 double knockout cells were more sensitive than wild type to oxidants (hydrogen peroxide and t-butyl hydroperoxide), but not to cis-platinum or gamma-irradiations. The low dosage oxidative stress resulted in more reduction of S phase and increase of G(2)/M phase in Myh(-/-)Ogg1(-/-) cells than in wild-type cells, but a similar level of cell death in both cells. The oxidants also induced more multinucleated cells in Myh(-/-)Ogg1(-/-) cells than in wild-type, accompanied by centrosome amplification and multipolar spindle formation. Thus, under oxidative stress, Myh and Ogg1 are likely required for normal cell-cycle progression and nuclear division, suggesting multiple roles of Myh and Ogg1 in the maintenance of genome stability and tumor prevention.
内源性和外源性来源产生的氧化应激会导致氧化性DNA损伤。在哺乳动物中，最常见的诱变碱基损伤7,8-二氢-8-氧代鸟嘌呤以及由此产生的错配腺嘌呤会被OGG1和MYH去除。人类MYH或小鼠MYH及OGG1的缺陷会导致肿瘤易感性，但潜在的分子机制尚未完全了解。为了便于研究MYH和OGG1在抵御氧化应激中的作用，我们构建了这些基因缺陷的小鼠胚胎成纤维细胞系。Myh和Ogg1双敲除细胞比野生型细胞对氧化剂（过氧化氢和叔丁基过氧化氢）更敏感，但对顺铂或γ射线不敏感。低剂量氧化应激导致Myh(-/-)Ogg1(-/-)细胞中S期的减少和G(2)/M期的增加比野生型细胞更多，但两种细胞中的细胞死亡水平相似。氧化剂还在Myh(-/-)Ogg1(-/-)细胞中比在野生型细胞中诱导产生更多的多核细胞，同时伴有中心体扩增和多极纺锤体形成。因此，在氧化应激下，Myh和Ogg1可能是正常细胞周期进程和核分裂所必需的，这表明Myh和Ogg1在维持基因组稳定性和预防肿瘤方面具有多种作用。
