Identification of essential yeast genes involved in polyamine resistance

Abstract

Polyamines such as spermine and spermidine perform multiple functions in cells and these include the regulation of transcription, protein and DNA syntheses, as well as the stabilization of DNA and RNA. At elevated concentrations, polyamines are toxic as catabolic processes via polyamine oxidases produce hydrogen peroxide and reactive aldehydes including acrolein that can damage proteins, DNA, and other cellular components. Efforts have been focused on the uptake of polyamines in order to identify targets that can transport polyamine analogs to destroy cancer cells. High throughput screens using the collection of yeast haploid mutants have revealed components of the plasma membrane including uptake transporters and effectors of the proton gradient that are involved in regulating polyamine toxicity. In this study, we used the collection of hypomorphic alleles of the essential genes downregulated by the Decreased Abundance by mRNA Perturbation (DAmP) strategy to search for strains with downregulated genes that display resistance to polyamines. We uncovered 115 DAmP strains that showed hyper-resistance to spermine. These DAmP strains were downregulated for genes encoding proteins that are involved in transcriptional regulation, RNA and DNA metabolisms. Our study identify new factors that can be modulated to sensitize cancer cells to polyamine analogs.