Rjd. Reid et al., CAMPTOTHECIN SENSITIVITY IS MEDIATED BY THE PLEIOTROPIC DRUG-RESISTANCE NETWORK IN YEAST, The Journal of biological chemistry, 272(18), 1997, pp. 12091-12099
The antineoplastic alkaloid camptothecin interferes with the catalytic
cycle of DNA topoisomerase I rendering it a cellular poison, Camptoth
ecin stabilizes a covalent enzyme-DNA intermediate that is converted i
nto lethal double strand DNA lesions during S phase of the cell cycle.
Yeast SCT1 mutants were isolated in a screen for mutations in genes o
ther than TOP1 that result in camptothecin resistance. Here we report
SCT1 is allelic to PDR1 and that a Thr-879 to Met substitution in the
PDR1-101 transcription factor confers multiple drug resistance. PDR1 r
egulates the expression of several gene products including the ATP-bin
ding cassette transmembrane transport proteins PDR5, YOR1, and SNQ2. T
he PDR1 T879M mutant increased PDR5 transcription compared with wild-t
ype PDR1 strains, Deletion of PDR1 or the downstream effector SNQ2 inc
reased cell sensitivity to camptothecin, whereas deletion of YOR1 or P
DR5 had little effect on camptothecin sensitivity, However, the campto
thecin resistance accompanying GAL1-promoted overexpression of PDR5 su
ggests some substrate promiscuity among the ATP-binding cassette trans
porters. These data underscore the role of the pleiotropic drug resist
ance network in regulating camptothecin toxicity and are consistent wi
th a model of decreased intracellular concentrations of camptothecin r
esulting from the increased expression of the SNQ2 transporter.