Human DNA glycosylase enzyme TDG repairs thymine mispaired with exocyclic etheno-DNA adducts
Human DNA glycosylase enzyme TDG repairs thymine mispaired with exocyclic etheno-DNA adducts
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DOI：
10.1016/j.freeradbiomed.2014.07.044
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发表时间：
2014-11-01
影响因子：
7.4
通讯作者：
Sugimura, Haruhiko
中科院分区：
文献类型：
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作者：
Goto, Masanori;Shinmura, Kazuya;Sugimura, Haruhiko
脂质过氧化直接与DNA反应，产生各种环外乙烯基DNA加合物，其中一些被认为有助于致癌。然而，人类修复它们的系统在很大程度上是未知的。我们假设乙烯基-DNA加合物通过DNA糖基化酶启动的碱基切除修复来修复。为了验证这一假设，我们检查了DNA糖基化酶蛋白OGG 1、SMUG 1、TDG、NEIL 1、MUTYH、NTH 1、MPG和UNG 2针对含有1，N-6-乙烯基腺嘌呤的双链寡核苷酸的活性（α-氨基-4-乙烯胞嘧啶），3，N-4-乙烯胞嘧啶丁酮-乙烯胞嘧啶（B C）、丁酮-乙烯鸟嘌呤（B G）、庚酮-乙烯胞嘧啶（H N C）或庚酮-乙烯鸟嘌呤（H N G）。我们发现，TDG能够在体外去除与胸腺嘧啶C、B胸腺嘧啶C、B胸腺嘧啶G、H胸腺嘧啶C或H胸腺嘧啶G错配的胸腺嘧啶。接下来我们检查了TDG对人类细胞中乙烯基DNA加合物的影响。TDG敲除细胞表现出以下特征：（a）对乙烯基-DNA加合物诱导引起的细胞死亡具有更高的抵抗力;（B）较低的BMP-C修复活性;（c）与对照细胞相比，BMP-C引起的突变适度加速。所有这些特征表明，TDG对人类细胞中的乙烯基-DNA加合物具有修复活性。这些结果表明，TDG对乙烯基DNA加合物具有新的修复活性。(C)2014爱思唯尔公司All rights reserved.
Lipid peroxidation directly reacts with DNA and produces various exocyclic etheno-base DNA adducts, some of which are considered to contribute to carcinogenesis. However, the system for repairing them in humans is largely unknown. We hypothesized that etheno-DNA adducts are repaired by base excision repair initiated by DNA glycosylase. To test this hypothesis, we examined the activities of the DNA glycosylase proteins OGG1, SMUG1, TDG, NEIL1, MUTYH, NTH1, MPG, and UNG2 against double-stranded oligonucleotides containing 1,N-6-ethenoadenine (epsilon A), 3,N-4-ethenocytosine (epsilon C), butanone-ethenocytosine (B epsilon C), butanone-ethenoguanine (B epsilon G), heptanone-ethenocytosine (H epsilon C), or heptanone-ethenoguanine (H epsilon G) using a DNA cleavage assay. We found that TDG is capable of removing thymine that has mispaired with epsilon C, B epsilon C, B epsilon G, H epsilon C, or H epsilon G in vitro. We next examined the effect of TDG against etheno-DNA adducts in human cells. TDG-knockdown cells exhibited the following characteristics: (a) higher resistance to cell death caused by the induction of etheno-DNA adducts; (b) lower repair activity for epsilon C; and (c) a modest acceleration of mutations caused by epsilon C, compared with the rate in control cells. All these characteristics suggest that TDG exerts a repair activity against etheno-DNA adducts in human cells. These results suggest that TDG has novel repair activities toward etheno-DNA adducts. (C) 2014 Elsevier Inc. All rights reserved.