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首页> 外文期刊>Cell cycle >Chromosome segregation and organization are targets of 5 '-Fluorouracil in eukaryotic cells
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Chromosome segregation and organization are targets of 5 '-Fluorouracil in eukaryotic cells

机译：染色体的分离和组织是真核细胞中5'-氟尿嘧啶的靶标

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摘要

The antimetabolite 5-Fluorouracil (5FU) is an analog of uracil commonly employed as a chemotherapeutic agent in the treatment of a range of cancers including colorectal tumors. To assess the cellular effects of 5FU, we performed a genome-wide screening of the haploid deletion library of the eukaryotic model Schizosaccharomyces pombe. Our analysis validated previously characterized drug targets including RNA metabolism, but it also revealed unexpected mechanisms of action associated with chromosome segregation and organization (post-translational histone modification, histone exchange, heterochromatin). Further analysis showed that 5FU affects the heterochromatin structure (decreased levels of histone H3 lysine 9 methylation) and silencing (down-regulation of heterochromatic dg/dh transcripts). To our knowledge, this is the first time that defects in heterochromatin have been correlated with increased cytotoxicity to an anticancer drug. Moreover, the segregation of chromosomes, a process that requires an intact heterochromatin at centromeres, was impaired after drug exposure. These defects could be related to the induction of genes involved in chromatid cohesion and kinetochore assembly. Interestingly, we also observed that thiabendazole, a microtubule-destabilizing agent, synergistically enhanced the cytotoxic effects of 5FU. These findings point to new targets and drug combinations that could potentiate the effectiveness of 5FU-based treatments.
机译：抗代谢物5-氟尿嘧啶（5FU）是尿嘧啶的类似物，通常用作治疗包括结直肠肿瘤在内的多种癌症的化学治疗剂。为了评估5FU的细胞效应，我们对真核模型粟酒裂殖酵母单倍体缺失文库进行了全基因组筛选。我们的分析验证了先前表征的包括RNA代谢在内的药物靶标，但它也揭示了与染色体分离和组织（翻译后组蛋白修饰，组蛋白交换，异染色质）相关的意想不到的作用机制。进一步的分析表明5FU影响异染色质结构（组蛋白H3赖氨酸9甲基化水平降低）和沉默（异色dg / dh转录本的下调）。据我们所知，这是首次将异染色质的缺陷与抗癌药的细胞毒性增加相关联。此外，在药物暴露后，染色体的分离被削弱了，这是一个需要在着丝粒处完整的异染色质的过程。这些缺陷可能与染色单体内聚力和线粒体组装相关基因的诱导有关。有趣的是，我们还观察到噻苯达唑（一种微管去稳定剂）协同增强了5FU的细胞毒性作用。这些发现指向可以增强基于5FU的治疗效果的新靶标和药物组合。

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