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Research article2013Peer reviewedOpen access

A Ham1p-Dependent Mechanism and Modulation of the Pyrimidine Biosynthetic Pathway can both Confer Resistance to 5-Fluorouracil in Yeast

Carlsson, Mattias; Gustavsson, Marie; Hu, Guo-Zhen; Murén, Eva; Ronne, Hans

Abstract

5-Fluorouracil (5-FU) is an anticancer drug and pyrimidine analogue. A problem in 5-FU therapy is acquired resistance to the drug. To find out more about the mechanisms of resistance, we screened a plasmid library in yeast for genes that confer 5-FU resistance when overexpressed. We cloned five genes: CPA1, CPA2, HMS1, YAE1 and YJL055W. CPA1 and CPA2 encode a carbamoyl phosphate synthase involved in arginine biosynthesis and HMS1 a helix-loop-helix transcription factor. Our results suggest that CPA1, CPA2, and HMS1 confer 5-FU resistance by stimulating pyrimidine biosynthesis. Thus, they are unable to confer 5-FU resistance in a ura2 mutant, and inhibit the uptake and incorporation into RNA of both uracil and 5-FU. In contrast, YAE1 and YJL055W confer 5-FU resistance in a ura2 mutant, and selectively inhibit incorporation into RNA of 5-FU but not uracil. YAE1 is the strongest resistance gene, but it partially depends on YJL055W for its function. This suggests that YAE1 and YJL055W function together in a novel mechanism for detoxification of 5-FU and other pyrimidine analogs. Yae1p belongs to a small protein family with only two members, which are conserved in all eukaryotes examined. One of the human homologs, TAOS1, is overexpressed in oral carcinomas.

Published in

PLoS ONE
2013, Volume: 8, number: 10Publisher: PUBLIC LIBRARY SCIENCE