Multiple pathways of recombination define cellular responses to cisplatin
Multiple pathways of recombination define cellular responses to cisplatin
复制标题
DOI：
10.1016/s1074-5521(00)00064-8
复制
发表时间：
2000-01-01
影响因子：
--
通讯作者：
Essigmann, JM
中科院分区：
文献类型：
--
作者：
Zdraveski, ZZ;Mello, JA;Essigmann, JM
背景：顺铂是一种DNA损伤药物，用于治疗睾丸肿瘤。顺铂的毒性可能源于其形成抑制聚合酶的DNA加合物的能力。被阻断的复制对致力于不懈分裂的肿瘤细胞来说是一个特别的挑战。重组提供了一种即使存在病变也可以进行复制的机制，因此对控制顺铂毒性具有重要意义。结果：与亲本菌株相比，重组缺陷的大肠杆菌突变株对顺铂非常敏感。我们的数据证实，子链间隙和双链断裂重组通路对顺铂治疗后的生存至关重要。虽然核苷酸切除修复(NER)被证实对顺铂的毒性有显著的保护作用，但大多数重组缺陷菌株与NER缺陷的uvrA突变体一样对药物敏感。重组/NER缺失的双突变体对顺铂的敏感性高于相应的单突变体，提示重组和NER途径在对抗顺铂毒性中起着独立的作用。与反式异构体和正构烷基化试剂相比，顺铂是一种有效的重组原。丝裂霉素C和顺铂一样，形成DNA交联链，在最低毒性剂量下也是重组的。结论：我们已经证明，所有主要的重组途径对顺铂处理后的大肠杆菌存活都是关键的。此外，重组途径独立于NER发挥作用，对NER具有同等重要的作用，作为对抗顺铂毒性的基因保护系统。综上所述，这些结果为细胞如何存活并屈服于这种广泛使用的抗癌药物提供了新的线索。
Background: Cisplatin is a DNA-damaging drug used for treatment of testicular tumors. The toxicity of cisplatin probably results from its ability to form DNA adducts that inhibit polymerases. Blocked replication represents a particular challenge for tumor cells, which are committed to unremitting division. Recombination provides a mechanism by which replication can proceed despite the presence of lesions and therefore could be significant for managing cisplatin toxicity.Results: Recombination-deficient Escherichia coli mutants were strikingly sensitive to cisplatin when compared with the parental strain. Our data identified both daughter-strand gap and double-strand break recombination pathways as critical for survival following treatment with cisplatin. Although it is established that nucleotide excision repair (NER) significantly protects against cisplatin toxicity, most recombination-deficient strains were as sensitive to the drug as the NER-deficient uvrA mutant. Recombination/NER deficient double mutants were more sensitive to cisplatin than the corresponding single mutants, suggesting that recombination and NER pathways play independent roles in countering cisplatin toxicity. Cisplatin was a potent recombinogen in comparison with the trans isomer and canonical alkylating agents. Mitomycin C, which like cisplatin, forms DNA cross-links, was also recombinogenic at minimally toxic doses.Conclusions: We have demonstrated that all of the major recombination pathways are critical for E. coli survival following treatment with cisplatin. Moreover, recombination pathways act independently of NER and are of equal importance to NER as genoprotective systems against cisplatin toxicity. Taken together, these results shed new light on how cells survive and succumb to this widely used anticancer drug.