Oxidative stress inactivates the human DNA mismatch repair system
Oxidative stress inactivates the human DNA mismatch repair system
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DOI：
10.1152/ajpcell.00422.2001
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发表时间：
2002-07-01
影响因子：
5.5
通讯作者：
Boland, CR
中科院分区：
文献类型：
--
作者：
Chang, CL;Marra, G;Boland, CR
在人DNA错配修复（MMR）系统中，hMSH 2分别与hMSH 6和hMSH 3形成hMutSalpha和hMutSbeta复合物，而hMLH 1和hPMS 2形成hMutLalpha异二聚体。这些复合物与MMR系统中的其他成分一起，纠正DNA复制过程中发生的单碱基错配和小插入/缺失环。微卫星不稳定性（MSI）是指由于MMR系统故障而导致DNA微卫星中的环未得到纠正。低频MSI（MSI-L）在一些慢性炎症组织中观察到，但MMR系统没有遗传失活。我们推测，与慢性炎症相关的氧化应激可能会损害MMR系统的蛋白质成分，导致其功能失活。在这项研究中，我们证明，非细胞毒性水平的H2 O2以剂量依赖的方式抑制单碱基错配和MMR系统的环修复活动。使用重组MMR蛋白的体外互补试验的基础上，我们表明，这种失活是最有可能由于氧化损伤hMutSalpha，hMutSbeta，和hMutLalpha蛋白复合物。我们推测，MMR功能的失活，在氧化应激反应可能是负责的MSI-L中看到的非肿瘤和癌症组织与慢性炎症。
In the human DNA mismatch repair (MMR) system, hMSH2 forms the hMutSalpha and hMutSbeta complexes with hMSH6 and hMSH3, respectively, whereas hMLH1 and hPMS2 form the hMutLalpha heterodimer. These complexes, together with other components in the MMR system, correct single-base mismatches and small insertion/deletion loops that occur during DNA replication. Microsatellite instability (MSI) occurs when the loops in DNA microsatellites are not corrected because of a malfunctioning MMR system. Low-frequency MSI (MSI-L) is seen in some chronically inflamed tissues in the absence of genetic inactivation of the MMR system. We hypothesize that oxidative stress associated with chronic inflammation might damage protein components of the MMR system, leading to its functional inactivation. In this study, we demonstrate that noncytotoxic levels of H2O2 inactivate both single-base mismatch and loop repair activities of the MMR system in a dose-dependent fashion. On the basis of in vitro complementation assays using recombinant MMR proteins, we show that this inactivation is most likely due to oxidative damage to hMutSalpha, hMutSbeta, and hMutLalpha protein complexes. We speculate that inactivation of the MMR function in response to oxidative stress may be responsible for the MSI-L seen in nonneoplastic and cancer tissues associated with chronic inflammation.