Abstract: UPC2 and ECM22 belong to a Zn(2)-Cys(6) family of fungal transcription factors and have been implicated in the regulation of sterol synthesis in Saccharomyces cerevisiae and Candida albicans. Previous reports suggest that double deletion of these genes in S. cerevisiae is lethal depending on the genetic background of the strain. In this investigation we demonstrate that lethality of upc2D ecm22D is attributable to a mutation in the HAP1 transcription factor commonly mutant in the S288C background. In addition we demonstrate that strains containing upc2D ecm22D are also inviable when carrying deletions of ERG6 and ERG28 but not when carrying deletions of ERG3, ERG4, or ERG5. It has previously been demonstrated that UPC2 and ECM22 regulate S. cerevisiae ERG2 and ERG3 and that the erg2D upc2D ecm22D triple mutant is also synthetically lethal. We employed transposon mutagenesis to isolate viable suppressors of hap1D, erg2D, erg6D and erg28D in the upc2D ecm22D genetic background. Mutations in two genes YND1 and GDA1 encoding apyrases were found to suppress the synthetic lethality of three of these triple mutants but not erg2D upc2D ecm22D. We show that deletion of YND1 like deletion of GDA1 alters the sphingolipids profiles suggesting that changes in sphingolipids compensate for lethality produced by changes in sterol composition and abundance.