hOGG1-Cys326 variant cells are hypersensitive to DNA repair inhibition by nitric oxide.
hOGG1-Cys326 variant cells are hypersensitive to DNA repair inhibition by nitric oxide.
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DOI：
10.1093/carcin/bgu066
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发表时间：
2014-06
期刊：
影响因子：
4.7
通讯作者：
Eva Moritz;K. Pauly;A. Bravard;Janet Hall;J. Radicella;B. Epe
中科院分区：
文献类型：
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作者：
Eva Moritz;K. Pauly;A. Bravard;Janet Hall;J. Radicella;B. Epe
哺乳动物细胞DNA中8-氧代-7，8-二氢鸟嘌呤的修复由8-氧代鸟嘌呤DNA糖基化酶（OGG 1）启动。人OGG 1基因中常见的多态性rs 1052133导致蛋白质氨基酸326处丝氨酸被半胱氨酸取代，并与某些人群中各种类型癌症的风险改变相关。OGG 1-Cys 326蛋白似乎具有正常的酶活性，但比丝氨酸变体对氧化更敏感。在这里，我们描述了两种OGG 1变体在炎症特征的应激条件下，即在用一氧化氮（NO）预处理或预暴露于高温的细胞中的细胞修复的比较。结果表明，在引起可忽略的DNA损伤和小的细胞毒性的浓度下，NO强烈降低过表达OGG 1-Cys 326变体的HeLa细胞的DNA中氧化嘌呤的修复率。修复的减少在过表达OGG 1-Ser 326变体的同基因细胞中不太明显。在来自两个OGG 1变体等位基因纯合子的供体的EBV转化的淋巴细胞中观察到类似的结果。与此相反，高血压引起的压力造成的修复迟缓，是独立的OGG 1多态性。NO在变异细胞中的修复抑制引起遗传不稳定性增加，测量为氧化剂暴露后微核形成增加。结果可以解释这种变异等位基因携带者的炎症组织恶性转化的风险更高。
The repair of 8-oxo-7,8-dihydroguanine in the DNA of mammalian cells is initiated by 8-oxoguanine DNA glycosylase (OGG1). A frequent polymorphism in the human OGG1 gene, rs1052133, causes the substitution of serine by cysteine at amino acid 326 of the protein and has been associated with an altered risk for various types of cancer in some populations. The OGG1-Cys326 protein appears to have normal enzymatic activity, but greater sensitivity to oxidation than the serine variant. Here, we describe a comparison of the cellular repair by the two OGG1 variants under stress conditions characteristic of inflammation, namely in cells pretreated with nitric oxide (NO) or pre-exposed to hyperthermia. The results show that NO at concentrations causing negligible DNA damage and little cytotoxicity strongly reduces the repair rates of oxidized purines in the DNA of HeLa cells overexpressing the OGG1-Cys326 variant. The reduction in repair was much less pronounced in isogenic cells overexpressing the OGG1-Ser326 variant. Similar results were observed in EBV-transformed lymphocytes from donors homozygous for the two OGG1 variant alleles. In contrast, hyperthermia-induced stress caused a repair retardation that was independent of the OGG1 polymorphism. The repair inhibition by NO in the variant cells gave rise to increased genetic instability, measured as increased micronuclei formation after oxidant exposure. The results could explain a higher risk of malignant transformation in inflamed tissues of carriers of this variant allele.