Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin.
Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin.
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DOI：
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发表时间：
1988-12
影响因子：
3.6
通讯作者：
W. Eng;L. Faucette;R. Johnson;R. Sternglanz
中科院分区：
文献类型：
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作者：
W. Eng;L. Faucette;R. Johnson;R. Sternglanz
出芽酵母酿酒酵母（Saccharomyces cerevisiae）和裂殖酵母粟酒裂殖酵母（Schizosaccharomyces pombe）都对喜树碱敏感，喜树碱是一种DNA拓扑异构酶I的抑制剂。酿酒酵母的一个DNA修复突变体rad52对该药物高度敏感。在这两个物种中，完全缺失该酶的拓扑异构酶I突变体对该药物完全有抗性。一个具有导致温度敏感型拓扑异构酶I的突变的菌株在其体内对喜树碱的反应中表现出温度依赖性。一个携带过量产生拓扑异构酶I的质粒的菌株对该药物高度敏感。即使在没有药物的情况下，rad52突变体也会因酶的过量产生而死亡。文中报道了这些菌株中的几个对喜树碱类似物、对DNA拓扑异构酶II抑制剂以及对其他药物的反应。根据药物延长拓扑异构酶I - DNA共价中间体的寿命（该中间体被DNA修复系统识别为DNA损伤）来讨论喜树碱的细胞毒性作用。
The budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe are both sensitive to camptothecin, an inhibitor of DNA topoisomerase I. An S. cerevisiae DNA repair mutant, rad52, is hypersensitive to the drug. In both species, topoisomerase I mutants totally lacking the enzyme are completely resistant to the drug. A strain with a mutation leading to a temperature-sensitive topoisomerase I exhibits temperature dependence in its in vivo response to camptothecin. A strain carrying a plasmid that overproduces topoisomerase I is hypersensitive to the drug. The rad52 mutant is killed by overproduction of the enzyme, even in the absence of the drug. The response of several of these strains to camptothecin analogs, to DNA topoisomerase II inhibitors, and to other drugs is reported. The cytotoxic effects of camptothecin are discussed in terms of the drug extending the lifetime of a topoisomerase I-DNA covalent intermediate, which is recognized as DNA damage by a DNA repair system.