Increased ROS generation in subsets of OGG1 knockout fibroblast cells
Increased ROS generation in subsets of OGG1 knockout fibroblast cells
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DOI：
10.1016/j.mad.2007.09.005
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发表时间：
2007-11-01
影响因子：
5.3
通讯作者：
Boldogh, Istvan
中科院分区：
文献类型：
--
作者：
Bacsi, Attila;Chodaczek, Grzegorz;Boldogh, Istvan
氧鸟苷DNA糖基酶(OGG1)是一种主要的碱基切除修复蛋白，负责从基因组中切除突变的8-氧鸟苷(8-oxoG)损伤。尽管OGG1的S很重要，但Ogg1缺失(Ogg1(-/-))小鼠的中等表型尚不清楚。这项研究探讨了Ogg1(-/-)细胞限制8-oxoG在其基因组中积累的机制。我们的数据显示，Ogg1(-/-)细胞的一部分表现出更高的ROS水平((ROS)-R-H细胞)，而类似于85%的Ogg1(-/-)细胞表现出生理水平的ROS((ROS)-R-L细胞)。Ogg1(-/-)细胞根据DCF荧光强度分选得到(ROS)-R-L和(ROS)-R-H细胞培养物。(ROS)-R-L细胞以与Ogg1(+/+)相当的速度增殖，并逐渐积累细胞，表现出更高的ROS和8-oxoG水平。(ROS)-R-L细胞的8-oxoG水平是(ROS)-R-H细胞的2.8倍(7-27倍)。(ROS)-R-H细胞的线粒体比(ROS)-R-L和Ogg1(+/+)细胞释放更多的H_2O_2，并被类凋亡过程清除。这些发现表明，在没有OGG1的情况下，一个监测系统被激活，从Ogg1(-/-)培养物中移除极端8-oxoG水平的细胞。Ogg1(-/-)小鼠的组织中是否存在类似的机制是未来研究的重点。爱思唯尔爱尔兰有限公司出版。
Oxoguanine DNA glycosylase (OGG1) is a major base excision repair protein responsible for excision of the mutagenic 8-oxoguanosine (8-oxoG) lesions from the genome. Despite OGG1's importance, the moderate phenotype of Ogg1-null (Ogg1(-/-)) mice is not well understood. This study addresses a mechanism by which Ogg1(-/-) cells limit accumulation of 8-oxoG in their genome. Our data reveal that a subset of Ogg1(-/-) cells shows higher ROS levels ((ROS)-R-H cells), while similar to 85% of Ogg1(-/-) cells exhibit physiological levels of ROS ((ROS)-R-L cells). Ogg1(-/-) cells were sorted based on their DCF fluorescence intensity to obtain (ROS)-R-L and (ROS)-R-H cell cultures. (ROS)-R-L cultures proliferated at a rate comparable to Ogg1(+/+) and gradually accumulated cells exhibiting increased ROS and 8-oxoG levels. (ROS)-R-L cells show a 2.8-fold increase in 8-oxoG level vs. (ROS)-R-H cells (7-27-fold). Mitochondria of (ROS)-R-H cells released more H2O2 than (ROS)-R-L and Ogg1(+/+) cells and were eliminated by apoptotic-like processes. These findings suggest that in the absence of OGG1, a surveillance system is activated that removes cells with extreme 8-oxoG levels from Ogg1(-/-) cultures. Whether similar mechanisms exists in tissues of Ogg1(-/-) mice is the focus of future investigations. Published by Elsevier Ireland Ltd.