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5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs.
Mol Cell Biol. 2004 Dec; 24(24):10766-76.MC

Abstract

The antimetabolite 5-fluorouracil (5FU) is a widely used chemotherapeutic for the treatment of solid tumors. Although 5FU slows DNA synthesis by inhibiting the ability of thymidylate synthetase to produce dTMP, the drug also has significant effects on RNA metabolism. Recent genome-wide assays for 5FU-induced haploinsufficiency in Saccharomyces cerevisiae identified genes encoding components of the RNA processing exosome as potential targets of the drug. In this report, we used DNA microarrays to analyze the effect of 5FU on the yeast transcriptome and found that the drug causes the accumulation of polyadenylated fragments of the 27S rRNA precursor and that defects in the nuclear exoribonuclease Rrp6p enhance this effect. The size distribution of these RNAs and their sensitivity to Rrp6p suggest that they are normally degraded by the nuclear exosome and a 5'-3' exoribonuclease. Consistent with this hypothesis, 5FU inhibits the growth of RRP6 mutants with defects in the degradation function of the enzyme and it interferes with the degradation of an rRNA precursor. The detection of poly(A)(+) pre-RNAs in strains defective in various steps in ribosome biogenesis suggests that the production of poly(A)(+) pre-rRNAs may be a general result of defects in rRNA processing. These findings suggest that 5FU inhibits an exosome-dependent surveillance pathway that degrades polyadenylated precursor rRNAs.

Authors+Show Affiliations

Department of Microbiology and Immunology, Box 672, 601 Elmwood Avenue, Rochester, NY 14642, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15572680

Citation

Fang, Feng, et al. "5-fluorouracil Enhances Exosome-dependent Accumulation of Polyadenylated RRNAs." Molecular and Cellular Biology, vol. 24, no. 24, 2004, pp. 10766-76.
Fang F, Hoskins J, Butler JS. 5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs. Mol Cell Biol. 2004;24(24):10766-76.
Fang, F., Hoskins, J., & Butler, J. S. (2004). 5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs. Molecular and Cellular Biology, 24(24), 10766-76.
Fang F, Hoskins J, Butler JS. 5-fluorouracil Enhances Exosome-dependent Accumulation of Polyadenylated RRNAs. Mol Cell Biol. 2004;24(24):10766-76. PubMed PMID: 15572680.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs. AU - Fang,Feng, AU - Hoskins,Jason, AU - Butler,J Scott, PY - 2004/12/2/pubmed PY - 2004/12/31/medline PY - 2004/12/2/entrez SP - 10766 EP - 76 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 24 IS - 24 N2 - The antimetabolite 5-fluorouracil (5FU) is a widely used chemotherapeutic for the treatment of solid tumors. Although 5FU slows DNA synthesis by inhibiting the ability of thymidylate synthetase to produce dTMP, the drug also has significant effects on RNA metabolism. Recent genome-wide assays for 5FU-induced haploinsufficiency in Saccharomyces cerevisiae identified genes encoding components of the RNA processing exosome as potential targets of the drug. In this report, we used DNA microarrays to analyze the effect of 5FU on the yeast transcriptome and found that the drug causes the accumulation of polyadenylated fragments of the 27S rRNA precursor and that defects in the nuclear exoribonuclease Rrp6p enhance this effect. The size distribution of these RNAs and their sensitivity to Rrp6p suggest that they are normally degraded by the nuclear exosome and a 5'-3' exoribonuclease. Consistent with this hypothesis, 5FU inhibits the growth of RRP6 mutants with defects in the degradation function of the enzyme and it interferes with the degradation of an rRNA precursor. The detection of poly(A)(+) pre-RNAs in strains defective in various steps in ribosome biogenesis suggests that the production of poly(A)(+) pre-rRNAs may be a general result of defects in rRNA processing. These findings suggest that 5FU inhibits an exosome-dependent surveillance pathway that degrades polyadenylated precursor rRNAs. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/15572680/5_fluorouracil_enhances_exosome_dependent_accumulation_of_polyadenylated_rRNAs_ DB - PRIME DP - Unbound Medicine ER -