Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells.
Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells.
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DOI：
10.1016/j.dnarep.2014.11.007
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发表时间：
2015-02
期刊：
影响因子：
3.8
通讯作者：
Doetsch, Paul W.
中科院分区：
文献类型：
--
作者：
Morreall, Jordan;Limpose, Kristin;Sheppard, Clayton;Kow, Yoke Wah;Werner, Erica;Doetsch, Paul W.
活性氧通过诱导氧化性DNA损伤威胁基因组的完整性。氧化性DNA损伤的一种常见形式是诱变损伤8-氧代鸟嘌呤（8-oxodG）。可诱导8-oxodG的氧化应激的一个驱动因素是炎症，其可由细胞因子肿瘤坏死因子α（TNF-α）引发。氧化性DNA损伤主要通过碱基切除修复途径修复，该途径由靶向特定DNA损伤的糖基化酶启动。8-oxodG被8-氧代鸟嘌呤糖基化酶1（OGG 1）切除。常见的Ogg 1等位基因变体是S326 C-Ogg 1，在亚洲和高加索人群中普遍存在。S326 C-Ogg 1与多种形式的癌症相关，并且S326 C-OGG 1通过氧化失活。然而，炎症细胞因子引起的氧化应激是否会损害OGG 1变体的修复活性仍然未知。我们研究了TNF-α是否引起氧化应激，通过半胱氨酸326氧化诱导DNA损伤并使S326 C-OGG 1失活。在小鼠胚胎成纤维细胞中，我们发现S326 C-OGG 1仅在暴露于H2 O2或TNF-α后失活。在氧化应激之前用抗氧化剂N-乙酰半胱氨酸治疗挽救了S326 C-OGG 1活性，这通过体外和细胞修复试验证明。相反，S326 C-OGG 1活性不受溴酸钾的影响，溴酸钾诱导氧化性DNA损伤而不引起氧化应激，可能是半胱氨酸氧化。这项研究表明，Cys 326易受氧化，使S326 C-OGG 1失活。生理学相关水平的TNF-α同时诱导8-oxodG和CINS 326 C-OGG 1。这些结果提示了一种可能导致S326 C-Ogg 1纯合子个体癌症风险增加的机制。
Reactive oxygen species threaten genomic integrity by inducing oxidative DNA damage. One common form of oxidative DNA damage is the mutagenic lesion 8-oxoguanine (8-oxodG). One driver of oxidative stress that can induce 8-oxodG is inflammation, which can be initiated by the cytokine tumor necrosis factor alpha (TNF-α). Oxidative DNA damage is primarily repaired by the base excision repair pathway, initiated by glycosylases targeting specific DNA lesions. 8-oxodG is excised by 8-oxoguanine glycosylase 1 (OGG1). A common Ogg1 allelic variant is S326C-Ogg1, prevalent in Asian and Caucasian populations. S326C-Ogg1 is associated with various forms of cancer, and S326C-OGG1 is inactivated by oxidation. However, whether oxidative stress caused by inflammatory cytokines compromises OGG1 variant repair activity remains unknown. We addressed whether TNF-α causes oxidative stress that both induces DNA damage and inactivates S326C-OGG1 via cysteine 326 oxidation. In mouse embryonic fibroblasts, we found that S326C-OGG1 was inactivated only after exposure to H2O2 or TNF-α. Treatment with the antioxidant N-acetylcysteine prior to oxidative stress rescued S326C-OGG1 activity, demonstrated by in vitro and cellular repair assays. In contrast, S326C-OGG1 activity was unaffected by potassium bromate, which induces oxidative DNA damage without causing oxidative stress, and presumably cysteine oxidation. This study reveals that Cys326 is vulnerable to oxidation that inactivates S326C-OGG1. Physiologically relevant levels of TNF-α simultaneously induce 8-oxodG and inactivate S326C-OGG1. These results suggest a mechanism that could contribute to increased risk of cancer among S326C-Ogg1 homozygous individuals.
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