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5-Fluorouracil Enhances Exosome-Dependent Accumulation of Polyadenylated rRNAs

机译：5-氟尿嘧啶增强依赖腺体的聚腺苷酸化rRNA的积累。

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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.
机译：抗代谢物5-氟尿嘧啶（5FU）是广泛用于实体瘤治疗的化学疗法。尽管5FU通过抑制胸苷酸合成酶产生dTMP的能力来减慢DNA的合成，但该药物对RNA的代谢也有重要的作用。最近的全基因组检测5FU在酿酒酵母中的单倍体功能不足，已确定编码RNA加工外泌体成分的基因为该药物的潜在靶标。在本报告中，我们使用DNA微阵列分析了5FU对酵母转录组的作用，发现该药物引起27S rRNA前体的聚腺苷酸化片段的积累，而核外核糖核酸酶Rrp6p的缺陷增强了这种作用。这些RNA的大小分布及其对Rrp6p的敏感性表明，它们通常会被核外泌体和5'-3'外切核糖核酸酶降解。与此假设一致，5FU抑制了具有降解功能的 RRP6 突变体的生长，并干扰了rRNA前体的降解。对核糖体生物发生各个步骤有缺陷的菌株中poly（A） + pre-RNA的检测表明，poly（A） + pre-rRNA的产生可能是一种rRNA加工缺陷的一般结果。这些发现表明5FU抑制了外泌体依赖性监视途径，该途径可降解多腺苷酸化的前体rRNA。

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