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Evidence for distinct DNA‐ and RNA‐based mechanisms of 5‐fluorouracil cytotoxicity in Saccharomyces cerevisiae

5‐Fluorouracil (5FU) is an effective chemotherapeutic drug developed as an inhibitor of thymidylate synthetase (TS). Inhibition of TS leads to ‘thymine‐less death’, a condition resulting from depletion of dTTP pools and misincorporation of dUTP into newly synthesized or repaired DNA. 5FU is also incorporated into RNA and a growing body of evidence suggests that RNA‐based effects play a significant role in its cytotoxicity. Indeed, recent experiments in yeast showed that defects in the nuclear RNA exosome subunit Rrp6p cause hypersensitivity to 5FU. The present study asked whether the 5FU hypersensitivity of an rrp6‐Δ yeast strain reflects the DNA‐ or RNA‐based effects of 5FU. Genetic analyses suggest that while a DNA repair mutation, apn1‐Δ, causes sensitivity to 5FU‐induced DNA damage, an rrp6‐Δ mutation causes hypersensitivity, due to the RNA‐based effects of 5FU. Analysis of a strain with normal DNA and RNA metabolism grown in the presence of 5FU shows that UMP suppresses the 5FU‐induced defect more than dTMP, suggesting that the RNA‐based toxicity of 5FU predominates in these cells. These findings underscore the importance of understanding the RNA‐based mechanism of 5FU cytotoxicity and highlight the use of yeast as a model system for elucidating its details. Copyright © 2007 John Wiley & Sons, Ltd.