SCT1 MUTANTS SUPPRESS THE CAMPTOTHECIN SENSITIVITY OF YEAST-CELLS EXPRESSING WILD-TYPE DNA TOPOISOMERASE-I

被引:63
作者
KAUH, EA [1 ]
BJORNSTI, MA [1 ]
机构
[1] THOMAS JEFFERSON UNIV,DEPT BIOCHEM & MOLEC BIOL,PHILADELPHIA,PA 19107
关键词
D O I
10.1073/pnas.92.14.6299
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Camptothecin is a potent antineoplastic agent that interferes with the action of eukaryotic DNA topoisomerase I; the covalent enzyme-DNA intermediate is reversibly stabilized, leading to G(2) arrest and cell death, We used a genetic screen to identify cellular factors, other than DNA topoisomerase I, that participate in the process of camptothecin-induced cell death, Following ethyl methanesulfonate mutagenesis of top 1 Delta yeast cells expressing plasmid-borne wild-type DNA topoisomerase I, six dominant suppressors of camptothecin toxicity were isolated that define a single genetic locus, sct1. Mutant SCT1 cells expressed DNA topoisomerase I protein of similar specific activity and camptothecin sensitivity to that of congenic, drug-sensitive sct1 cells, yet were resistant to camptothecin-mediated lethality. Moreover, camptothecin-treated SCT1 cells did not exhibit the G(2)-arrested, terminal phenotype characteristic of drug-treated wild-type cells, SCT1 cell sensitivity to other DNA-damaging agents suggests that alterations in SCT1 function suppress camptothecin-induced DNA damage produced in the presence of yeast DNA topoisomerase I.
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页码:6299 / 6303
页数:5
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