{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T11:38:25Z","timestamp":1775302705133,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2006,7,17]],"date-time":"2006-07-17T00:00:00Z","timestamp":1153094400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Yeast"],"published-print":{"date-parts":[[2006,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>5\u2010Fluorocytosine (5\u2010FC), a medically applied antifungal agent (Ancotil<jats:sup>\u00ae<\/jats:sup>), is also active against the model organism <jats:italic>Saccharomyces cerevisiae<\/jats:italic>. 5\u2010FC uptake in <jats:italic>S. cerevisiae<\/jats:italic> was considered to be mediated by the <jats:italic>FCY2<\/jats:italic>\u2010encoded cytosine\/adenine permease. By applying a highly sensitive assay, a low\u2010level but dose\u2010dependent toxicity of 5\u2010FC in <jats:italic>fcy2<\/jats:italic> mutants was detected, whereas cells deficient in the cytosine deaminase (encoded by <jats:italic>FCY1<\/jats:italic>), which is essential for intracellular conversion of 5\u2010FC to 5\u2010fluorouracil, display strong dose\u2010independent resistance. Thus, an alternative, Fcy2\u2010independent access pathway for 5\u2010FC exists in <jats:italic>S. cerevisiae<\/jats:italic>. A genome\u2010wide search for cytosine permease homologues identified two uncharacterized candidate genes, designated <jats:italic>FCY21<\/jats:italic> and <jats:italic>FCY22<\/jats:italic>, both of which exhibit highest similarity to <jats:italic>FCY2<\/jats:italic>. Disruption of either <jats:italic>FCY21<\/jats:italic> or <jats:italic>FCY22<\/jats:italic> resulted in strains displaying low\u2010level resistance, indicating the functional involvement of both gene products in 5\u2010FC toxicity. When mutations in <jats:italic>FCY21<\/jats:italic> or <jats:italic>FCY22<\/jats:italic> were combined with the <jats:italic>FCY2<\/jats:italic> disruption, both double mutants displayed stronger resistance when compared to the <jats:italic>FCY2<\/jats:italic> mutant alone. Disruptions in all three permease genes consequently conferred the highest degree of resistance, not only towards 5\u2010FC but also to the toxic adenine analogon 8\u2010azaadenine. As residual 5\u2010FC sensitivity was, however, even detectable in the <jats:italic>fcy2 fcy21 fcy22<\/jats:italic> mutant, we analysed the relevance of other <jats:italic>FCY2<\/jats:italic> homologues, i.e. <jats:italic>TPN1, FUR4, DAL4, FUI1<\/jats:italic> and <jats:italic>yOR071c<\/jats:italic>, for 5\u2010FC toxicity. Among these, Tpn1, Fur4 and the one encoded by <jats:italic>yOR071c<\/jats:italic> were found to contribute significantly to 5\u2010FC toxicity, thus revealing alternative entry routes for 5\u2010FC via other cytosine\/adenine permease homologues. 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