Links between DNA polymerase beta expression and sensitivity to bleomycin
Links between DNA polymerase beta expression and sensitivity to bleomycin
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DNA 聚合酶 β 表达与博莱霉素敏感性之间的联系
DOI：
10.1016/j.tox.2011.01.008
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发表时间：
2011-03-15
期刊：
影响因子：
4.5
通讯作者：
Zhang, Zunzhen
中科院分区：
文献类型：
--
作者：
Liu, Shukun;Lai, Yanhao;Zhang, Zunzhen
博来霉素（BLM）是一种重要的抗肿瘤抗生素，通过活性氧（ROS）介导的DNA氧化损伤使细胞死亡。然而，细胞耐药性的增加已成为其临床应用的严重限制。碱基切除修复（BER）是修复氧化碱基的主要途径，与DNA损伤性抗癌药物的耐药性有关。DNA聚合酶β（polymerase beta，pol β）是一种重要的BER酶，在BLM诱导的DNA氧化损伤中起重要作用，抑制pol β可增加BLM对DNA的敏感性。为了验证这一假设，我们使用具有不同pol β表达水平（野生型，pol β缺乏）的小鼠胚胎成纤维细胞（MEFs）评估了对BLM的敏感性，并探讨了潜在的机制。结果表明，当用相同剂量的BLM处理时，pol β缺陷型MEFs的细胞活力显著低于同基因野生型MEFs。此外，在pol β缺陷细胞中观察到ROS水平增加、DNA单链断裂和染色体断裂，表明在pol β缺陷下DNA修复受损和氧化DNA损伤增强。与研究结果一致，在pol β缺失细胞中也检测到增强的hprt基因突变频率。总之，本研究表明BLM诱导的DNA损伤可以通过BER途径修复，而pol β的缺失会导致DNA/染色体氧化损伤和基因突变，从而导致BLM超敏反应。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Bleomycin (BLM), an important anti-tumor antibiotic, enables cell death through oxidative DNA damage mediated by reactive oxygen species (ROS). However, increasing cellular resistance has become a serious limitation to its clinical application. Base excision repair (BER), the major pathway for repairing oxidative bases, is involved in resistance of DNA-damaging anticancer drugs. DNA polymerase beta (pol beta), a critical BER enzyme, has been reported to play a crucial role in combating BLM-induced oxidative DNA damage, as a result, pol beta inhibition may increase the sensitivity to BLM. To test this hypothesis, we evaluated the sensitivity to BLM using mouse embryo fibroblasts (MEFs) with distinct pol beta expression levels (wild-type, pol beta deficiency) and explored the underlying mechanisms. The results showed that cell viability of pol beta-deficient MEFs was significantly lower than that of isogenic wild type when treated with the same BLM dosage. In addition, increased ROS level, DNA single strand breaks, and chromosomal breakage were observed in pol beta deficient cells, indicating impaired DNA repair and enhanced oxidative DNA damage under pol beta deficiency. In agreement with the findings, an enhanced hprt gene mutation frequency was also detected in pol beta null cells. In summary, this study demonstrated that BLM-induced DNA damage could be repaired through BER pathway and absence of pol beta allows oxidative DNA/chromosome damage and gene mutation, which contributes to BLM hypersensitivity. (C) 2011 Elsevier Ireland Ltd. All rights reserved.