Volume 272, Number 18,
Issue of May 2, 1997
pp. 12091-12099
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Camptothecin Sensitivity Is Mediated by the Pleiotropic Drug
Resistance Network in Yeast
(Received for publication, November 22, 1996, and in revised form, February 24, 1997)
Robert J. D.
Reid
,
Eunkyung A.
Kauh
and
Mary-Ann
Bjornsti
From the Department of Biochemistry and Molecular Pharmacology,
Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
The antineoplastic alkaloid camptothecin
interferes with the catalytic cycle of DNA topoisomerase I rendering it
a cellular poison. Camptothecin stabilizes a covalent enzyme-DNA
intermediate that is converted into lethal double strand DNA lesions
during S phase of the cell cycle. Yeast SCT1 mutants were
isolated in a screen for mutations in genes other 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 regulates the expression of several gene products including the
ATP-binding cassette transmembrane transport proteins PDR5, YOR1, and
SNQ2. The PDR1 T879M mutant increased PDR5
transcription compared with wild-type PDR1 strains. Deletion of PDR1 or the downstream effector
SNQ2 increased cell sensitivity to camptothecin, whereas
deletion of YOR1 or PDR5 had little effect on
camptothecin sensitivity. However, the camptothecin resistance
accompanying GAL1-promoted overexpression of
PDR5 suggests some substrate promiscuity among the
ATP-binding cassette transporters. These data underscore the role of
the pleiotropic drug resistance network in regulating camptothecin
toxicity and are consistent with a model of decreased intracellular
concentrations of camptothecin resulting from the increased expression
of the SNQ2 transporter.
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