RT Journal Article SR Electronic T1 Inactivation of the Saccharomyces cerevisiae SKY1Gene Induces a Specific Modification of the Yeast Anticancer Drug Sensitivity Profile Accompanied by a Mutator Phenotype JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 659 OP 666 DO 10.1124/mol.61.3.659 VO 61 IS 3 A1 Paul W. Schenk A1 Antonius W. M. Boersma A1 Mariël Brok A1 Herman Burger A1 Gerrit Stoter A1 Kees Nooter YR 2002 UL http://molpharm.aspetjournals.org/content/61/3/659.abstract AB The therapeutic potential of the highly active anticancer agent cisplatin is severely limited by the occurrence of cellular resistance. A better understanding of the molecular pathways involved in cisplatin-induced cell death could potentially indicate ways to overcome cellular unresponsiveness to the drug and thus lead to better treatment results. We used the budding yeast Saccharomyces cerevisiae as a model organism to identify and characterize novel genes involved in cisplatin-induced cell kill, and found thatSKY1 (SR-protein-specific kinase from budding yeast) is a cisplatin sensitivity gene whose disruption conferred cisplatin resistance. In cross-resistance studies, we observed resistance of yeast sky1Δ cells (i.e., cells from which theSKY1 gene had been disrupted) to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil. Furthermore, these cells did not display reduced platinum accumulation, DNA platination or doxorubicin accumulation, indicating that the resistance is unrelated to decreased drug import or increased drug export. Based on the modification of the anticancer drug sensitivity profile and our finding that sky1Δ cells display a mutator phenotype, we propose that Sky1p might play a significant role in specific repair and/or tolerance pathways. Disruption of the S. cerevisiae SKY1 gene would thus result in deregulation of such mechanisms and, consequently, lead to altered drug sensitivity.