Role of DNA Polymerase Beta in the Genotoxicity of Arsenic
Role of DNA Polymerase Beta in the Genotoxicity of Arsenic
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DOI：
10.1002/em.20643
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发表时间：
2011-07-01
影响因子：
2.8
通讯作者：
Zhang, Zunzhen
中科院分区：
文献类型：
--
作者：
Lai, Yanhao;Zhao, Wei;Zhang, Zunzhen
砷是环境中的一种重要危害，与人类癌症和其他退行性疾病有关。然而，砷有害影响的机制仍不清楚。据报道，砷暴露会导致细胞活性氧增加和氧化性 DNA 损伤。这表明DNA碱基切除修复（BER）是修复氧化DNA损伤的主要途径，可能参与对抗砷的危害作用。作为 BER 中的关键修复酶，DNA 聚合酶 beta (Pol beta) 可能在降低砷毒性方面发挥重要作用。为了检验这一假设，我们评估了 Pol beta 缺乏下砷诱导的细胞毒性和基因毒性作用。我们的结果表明，用亚砷酸盐 (As(3+)) 处理后，Pol β 缺陷型小鼠胚胎成纤维细胞的活力远低于 Pol β 野生型细胞。 Pol beta 缺陷细胞中 DNA 损伤水平增加，亚砷酸盐诱导的 DNA 损伤修复显着延迟，表明 Pol beta 缺陷下 DNA 损伤的修复减少。这与微核 (MN) 频率的增加一致，微核是染色体断裂的指标，在用亚砷酸盐处理的 Pol β 缺陷细胞中也观察到了这一现象。相比之下，与 Pol beta 野生型细胞相比，过度表达 Pol beta 的细胞导致的 DNA 损伤和 MN 水平较低，表明该酶的过度表达可以对抗砷诱导的基因毒性作用。总之，我们的结果表明 Pol beta 在修复亚砷酸盐诱导的 DNA 损伤和维持染色体完整性方面发挥着重要作用，并进一步表明 BER 缺陷可能与砷的遗传毒性和致癌性有关。环境。摩尔。诱变剂。 52:460-468, 2011。(C) 2011 Wiley-Liss, Inc.
Arsenic, an important hazard in the environment, is associated with human cancer and other degenerative diseases. However, the mechanisms underlying arsenic hazardous effects remain unclear. It has been reported arsenic exposure can result in increased cellular reactive oxygen species and oxidative DNA damage. This suggests DNA base excision repair (BER), the major pathway for repairing oxidative DNA damage, may be involved in combating arsenic hazardous effects. As a critical repair enzyme in BER, DNA polymerase beta (Pol beta) might play an essential role in reducing arsenic toxicity. To test this hypothesis, we evaluated arsenic-induced cytotoxic and genotoxic effects under Pol beta deficiency. Our results demonstrated that the viability of Pol beta-deficient mouse embryonic fibroblasts was much lower than that of Pol beta wild-type cells after treatment with arsenite (As(3+)). An increased level of DNA damage and significantly delayed arsenite-induced DNA damage repair in Pol beta-deficient cells indicated reduced repair of DNA lesions under Pol beta deficiency. This was consistent with the increase in the frequency of micronuclei (MN), an indicator of chromosomal breakage, which was also observed in Pol beta-deficient cells treated with arsenite. In contrast, cells harboring overexpressed Pol beta resulted in a lower level of DNA damage and MN than Pol beta wild-type cells, indicating overexpression of the enzyme can combat arsenic-induced genotoxic effects. In conclusion, our results indicate an important role for Pol beta in repairing arsenite-induced DNA damage and maintaining chromosomal integrity and further suggest deficiency of BER may be involved in arsenic genotoxicity and carcinogenicity. Environ. Mol. Mutagen. 52:460-468, 2011. (C) 2011 Wiley-Liss, Inc.