Eng W K, Faucette L, Johnson R K, Sternglanz R
Department of Biochemistry, State University of New York, Stony Brook 11794.
Mol Pharmacol. 1988 Dec;34(6):755-60.
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.
出芽酵母酿酒酵母和裂殖酵母粟酒裂殖酵母对喜树碱（一种DNA拓扑异构酶I抑制剂）均敏感。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，完全缺乏该酶的拓扑异构酶I突变体对该药物完全耐药。一个因突变导致拓扑异构酶I温度敏感的菌株在其对喜树碱的体内反应中表现出温度依赖性。携带过量表达拓扑异构酶I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突变体也会因该酶的过量表达而死亡。报道了其中几种菌株对喜树碱类似物、DNA拓扑异构酶II抑制剂和其他药物的反应。从药物延长拓扑异构酶I-DNA共价中间体寿命的角度讨论了喜树碱的细胞毒性作用，该中间体被DNA修复系统识别为DNA损伤。
