Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation.
Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation.
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DOI：
10.1093/carcin/bgn033
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发表时间：
2008-04
期刊：
影响因子：
4.7
通讯作者：
Yali Xie;Hanjing Yang;Jeffrey H. Miller;D. Shih;G. Hicks;Jiuyong Xie;R. Shiu
中科院分区：
文献类型：
--
作者：
Yali Xie;Hanjing Yang;Jeffrey H. Miller;D. Shih;G. Hicks;Jiuyong Xie;R. Shiu
内源性和外源性氧化应激可引起DNA氧化损伤。在哺乳动物中，最常见的致突变碱基损伤7，8-二氢-8-氧代鸟嘌呤和由此产生的错配腺嘌呤被OGG 1和MYH去除。人类MYH或小鼠MYH和OGG 1的缺陷导致肿瘤易感性，但其潜在的分子机制尚未完全了解。为了便于研究MYH和OGG 1在抗氧化应激保护中的作用，我们产生了这些基因缺陷的小鼠胚胎成纤维细胞系。Myh和Ogg 1双基因敲除细胞比野生型更敏感的氧化剂（过氧化氢和叔丁基氢过氧化物），但不顺铂或γ射线。低剂量氧化应激导致Myh（-/-）Ogg 1（-/-）细胞S期缩短，G（2）/M期延长，但两种细胞死亡水平相似。氧化剂也诱导更多的多核细胞Myh（-/-）Ogg 1（-/-）细胞比野生型，伴随着中心体扩增和多极纺锤体形成。因此，在氧化应激下，Myh和Ogg 1可能是正常细胞周期进展和核分裂所必需的，这表明Myh和Ogg 1在维持基因组稳定性和预防肿瘤中具有多种作用。
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.