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A Ham1p-Dependent M...
A Ham1p-Dependent Mechanism and Modulation of the Pyrimidine Biosynthetic Pathway can both Confer Resistance to 5-Fluorouracil in Yeast
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- Carlsson, Mattias (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för mikrobiologi,Department of Microbiology
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- Gustavsson, Marie (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Hu, Guo-Zhen (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för mikrobiologi,Department of Microbiology
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- Murén, Eva (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Ronne, Hans (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för mikrobiologi,Department of Microbiology
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(creator_code:org_t)
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- 2013-10-04
- 2013
- English.
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e52094-
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Abstract
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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