Novel Circuitry Governing Emergence of Multidrug Resistance in Yeast

Abstract

Alternative splicing - a process by which a single gene gives rise to different protein newlineisoforms in eukaryotes has been implicated in many basic cellular processes, but little newlineis known about its role in drug resistance and fungal pathogenesis. The most common newlinehuman fungal pathogen, Candida albicans, has introns in 6 to 8% of its genes, the newlinefunctions of which remain largely unknown. Here we report alternative splicing newlineregulating drug resistance in Candida albicans. Comparative RNA-sequencing of two newlinedifferent sets of sequential, isogenic azole-sensitive and resistant isolates of Candida newlinealbicans revealed differential expression of splice isoforms of 14 genes. One of these was newlinethe superoxide dismutase genes SOD3, which contains a single intron. The sod3D/D newlinemutant was susceptible to the antifungals amphotericin B (AMB) and menadione (MND). newlineWhile AMB susceptibility was rescued by overexpression of both the spliced and newlineunspliced SOD3 isoforms, only the spliced isoform could overcome MND susceptibility, newlinedemonstrating the functional relevance of this splicing in developing drug resistance. newline