Ea. Kauh et Ma. Bjornsti, SCT1 MUTANTS SUPPRESS THE CAMPTOTHECIN SENSITIVITY OF YEAST-CELLS EXPRESSING WILD-TYPE DNA TOPOISOMERASE-I, Proceedings of the National Academy of Sciences of the United Statesof America, 92(14), 1995, pp. 6299-6303
Camptothecin is a potent antineoplastic agent that interferes with the
action of eukaryotic DNA topoisomerase I; the covalent enzyme-DNA int
ermediate is reversibly stabilized, leading to G(2) arrest and cell de
ath, 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 to
p 1 Delta yeast cells expressing plasmid-borne wild-type DNA topoisome
rase I, six dominant suppressors of camptothecin toxicity were isolate
d that define a single genetic locus, sct1. Mutant SCT1 cells expresse
d DNA topoisomerase I protein of similar specific activity and camptot
hecin sensitivity to that of congenic, drug-sensitive sct1 cells, yet
were resistant to camptothecin-mediated lethality. Moreover, camptothe
cin-treated SCT1 cells did not exhibit the G(2)-arrested, terminal phe
notype characteristic of drug-treated wild-type cells, SCT1 cell sensi
tivity to other DNA-damaging agents suggests that alterations in SCT1
function suppress camptothecin-induced DNA damage produced in the pres
ence of yeast DNA topoisomerase I.