A Genome-Wide Screening in Saccharomyces cerevisiae for Genes That Confer Resistance to the Anticancer Agent Cisplatin

• DOI: 10.1006/bbrc.2000.2361
• Publication Date: 2002-09-16T14:49:19Z
• Authors: Herman Burger; Astrid Capello; Paul W Schenk; Gerrit Stoter; Jaap Brouwer; Kees Nooter
• Keywords: Genomic Library; 0303 health sciences; Ultraviolet Rays; Genes, Fungal; Chromosome Mapping; Drug Resistance, Microbial; Saccharomyces cerevisiae; 3. Good health; Open Reading Frames; 03 medical and health sciences; Transformation, Genetic; EMC MM-03-86-08; Mutagenesis; Chromosomes, Fungal; Cisplatin; Genome, Fungal

Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model organism to study cisplatin resistance mechanisms and describe a one-step cisplatin selection to identify and characterize novel cisplatin resistance genes. Screening a multicopy yeast genomic library enabled us to isolate several yeast clones for which we could confirm that the cisplatin resistance phenotype was linked to the introduced fragment. In a first attempt, a number of open reading frames could be identified. Among these genes, PDE2 and ZDS2 were repeatedly identified as genes whose overexpression confers cellular resistance to cisplatin. PDE2, encoding cAMP-phosphodiesterase 2, is of particular interest because the overexpression of this yeast gene is known to induce cisplatin resistance in mammalian cells as well, providing proof of the principle of our experimental approach. In addition, the identification of PDE2 shows that our yeast screening system can directly be informative for drug resistance in mammalian cells.