Gustavsson M~Ronne H, 2008

Pubmed ID 18314501
Title Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast.
Authors Marie Gustavsson, Hans Ronne
Abstract We have screened a collection of haploid yeast knockout strains for increased sensitivity to 5-fluorouracil (5-FU). A total of 138 5-FU sensitive strains were found. Mutants affecting rRNA and tRNA maturation were particularly sensitive to 5-FU, with the tRNA methylation mutant trm10 being the most sensitive mutant. This is intriguing since trm10, like many other tRNA modification mutants, lacks a phenotype under normal conditions. However, double mutants for nonessential tRNA modification enzymes are frequently temperature sensitive, due to destabilization of hypomodified tRNAs. We therefore tested if the sensitivity of our mutants to 5-FU is affected by the temperature. We found that the cytotoxic effect of 5-FU is strongly enhanced at 38 degrees C for tRNA modification mutants. Furthermore, tRNA modification mutants show similar synthetic interactions for temperature sensitivity and sensitivity to 5-FU. A model is proposed for how 5-FU kills these mutants by reducing the number of tRNA modifications, thus destabilizing tRNA. Finally, we found that also wild-type cells are temperature sensitive at higher concentrations of 5-FU. This suggests that tRNA destabilization contributes to 5-FU cytotoxicity in wild-type cells and provides a possible explanation why hyperthermia can enhance the effect of 5-FU in cancer therapy.
Citation RNA 2008; 14:666-74


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Paper Phenotype Condition Medium Collection Tested mutants Data Details
Gustavsson M~Ronne H, 2008 growth (spot assay) 5-fluorouracil [15 ug/mL] SC + Leu hap alpha ~4,676 Discrete

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Nov. 18, 2014 Not available.