Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions
Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions
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DOI：
10.1038/jcbfm.2010.147
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发表时间：
2011-02-01
影响因子：
6.3
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
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作者：
Liu, Dong;Croteau, Deborah L.;Mattson, Mark P.
7，8-二氢-8-氧代鸟嘌呤DNA糖基化酶（OGG 1）是一种主要的DNA糖基化酶，参与核DNA和线粒体DNA（mtDNA）氧化损伤的碱基切除修复（BER）。我们使用OGG 1缺陷（OGG 1（-/-））小鼠来研究OGG 1在神经元对缺血和氧化应激的脆弱性中的可能作用。暴露后的培养神经元的氧化和代谢应激水平的OGG 1在细胞核中升高，线粒体表现出碎片和线粒体分裂蛋白动力相关蛋白1（Drp 1）的水平增加和膜电位降低。从OGG 1（-/-）小鼠中分离的皮质神经元比OGG 1（+/+）神经元更容易受到氧化损伤，并且与OGG 1（+/+）小鼠相比，OGG 1（-/-）小鼠在永久性大脑中动脉闭塞后出现更大的皮质梗死和行为缺陷。在同侧和对侧半球中，氧化性DNA碱基损伤（8-oxoG、FapyAde和FapyGua）的积累响应于缺血而升高，并且与OGG 1（+/+）小鼠相比，OGG 1（-/-）小鼠的对侧皮质中的程度更大。缺血诱导的8-oxoG切口活性升高涉及核亚型OGG 1水平的增加，表明对氧化性核DNA损伤的适应性反应。因此，OGG 1在缺血条件下修复核DNA的氧化损伤中具有关键作用，从而减少脑损伤并改善功能结果。Journal of Cerebral Blood Flow & Metabolism（2011）31，680-692; doi：10.1038/jcbfm.2010.147; 2010年8月25日在线发表
7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1(-/-) mice compared with OGG1(+/+) mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 680-692; doi:10.1038/jcbfm.2010.147; published online 25 August 2010