A New Genetic Pathway Mediating Multidrug Resistance in the Yeast Saccharomyces Cerevisiae

Abstract

Multiple drug resistance is quickly becoming an obstacle to the treatment of disease. Bacteria, parasitic protazoa, yeast and mammalian cancer cells develop mutations that render them resistant to a wide variety of structurally and chemically different compounds. In the yeast Saccharomyces cerevisiae, one of the main mechanisms causing drug resistance is the loss of function of ABC transporters that are responsible for effluxing the drug from the cell. The main ABC transporter responsible for efflux of many different drugs is Pdr5p. However, earlier work (Fleckenstein et.al. 1999; Shallom and Golin, 1996) shows that this is not the only pathway mediating resistance to these drugs. The global regulator Sin4p and the transcription factor YRRI operate in a PDR5-independent pathway to confer drug resistance to the cell. While wild type YRRI is not required for multidrug resistance, a gain-of¬function mutation in this gene can restore resistance in a previously drug hypersensitive Apdr5 mutant. This resistance requires both Sin4p, a member of the RNA Polymerase Mediator complex and Snf5p, a component of the chromatin remodeling complex SWIISNF. Disruption of these genes can cause profound drug hypersensitivity that cannot be explained by the changes in PDR5 transcription or function observed. Furthermore, loss of function mutations in either of these genes does not cause the increase in drug accumulation that is seen in a Opdr5 mutant. The SNF5, SIN4 and YRRI genes define a new, major pathway required for mediating multidrug resistance. This dissertation by Anne E Fleckenstein fulfills the dissertation requirement for the doctoral degree in Cellular and Microbial Biology approved by John Golin, Ph.D., as Director, and by James Greene, Ph.D. and Pamela Tuma, Ph.D. as Readers.