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Camptothecin sensitivity is mediated by the pleiotropic drug resistance network in yeast

R J Reid1, E A Kauh, M A Bjornsti

  • 1Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

The Journal of Biological Chemistry
|May 2, 1997
PubMed

Insights

The yeast SCT1 gene, identified as PDR1, confers resistance to camptothecin by regulating drug efflux pumps. A specific PDR1 mutation enhances the expression of these transporters, reducing intracellular camptothecin levels.

Area of Science:

  • Molecular biology
  • Genetics
  • Biochemistry

Background:

  • Camptothecin is an antineoplastic alkaloid that inhibits DNA topoisomerase I, leading to DNA damage and cell death.
  • Yeast mutants resistant to camptothecin were screened to identify genes other than TOP1 involved in resistance mechanisms.

Purpose of the Study:

  • To identify and characterize genes that confer camptothecin resistance in yeast.
  • To elucidate the role of the PDR1 gene and its associated drug efflux transporters in camptothecin sensitivity.

Main Methods:

  • Isolation and characterization of yeast SCT1 mutants conferring camptothecin resistance.
  • Genetic analysis to determine allelism between SCT1 and PDR1.
  • Assessing the impact of PDR1 mutations and transporter gene deletions/overexpression on camptothecin sensitivity.

Main Results:

  • The SCT1 gene was found to be allelic to PDR1, with a Thr-879 to Met substitution in PDR1 conferring multiple drug resistance.
  • The PDR1 T879M mutant increased the transcription of ATP-binding cassette transporters, including PDR5 and SNQ2.
  • Deletion of PDR1 or SNQ2 increased sensitivity to camptothecin, while deletion of YOR1 or PDR5 had minimal effect.

Conclusions:

  • The pleiotropic drug resistance (PDR) network, regulated by PDR1, plays a significant role in camptothecin toxicity.
  • Increased expression of the SNQ2 transporter likely reduces intracellular camptothecin concentrations, contributing to resistance.

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