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首页> 外文期刊>Nature >Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy
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Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy

机译：Hsp90应激通过诱导非整倍性增强了细胞的快速适应性

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摘要

Aneuploidy-the state of having uneven numbers of chromosomes-is a hallmark of cancer and a feature identified in yeast from diverse habitats. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could induce aneuploidy in budding yeast (Saccharomyces cerevisae). We show that whereas diverse stress conditions can induce an increase in chromosome instability, proteotoxic stress, caused by transient Hsp90 (also known as Hsp82 or Hsc82) inhibition or heat shock, markedly increased chromosome instability to produce a cell population with high karyotype diversity. The induced chromosome instability is linked to an evolutionarily conserved role for the Hsp90 chaperone complex in kinetochore assembly. Continued growth in the presence of an Hsp90 inhibitor resulted in the emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress potentiated fast adaptation to unrelated cytotoxic compounds by means of different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fuelling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress.
机译：非整倍体-染色体数目不均匀的状态-是癌症的标志，也是来自不同栖息地的酵母菌中鉴定出的特征。最近的研究表明，非整倍性是一种大突变的形式，能够在不同的应激条件下赋予适应性表型。在这里，我们研究了多效性应力是否可以在发芽酵母（酿酒酵母）中诱导非整倍性。我们显示，虽然各种应激条件可能会导致染色体不稳定性增加，但由瞬时Hsp90（也称为Hsp82或Hsc82）抑制或热激引起的蛋白毒性应激会显着增加染色体不稳定性，从而产生具有高核型多样性的细胞群。诱导的染色体不稳定性与在线粒体组装过程中Hsp90伴侣复合物在进化上的保守作用有关。在Hsp90抑制剂存在下持续生长导致出现具有XV染色体增益的耐药菌落。这种抗药性表型是一种定量性状，涉及位于XV染色体上的至少两个基因的拷贝数增加。短期暴露于Hsp90胁迫可通过不同的非整倍体染色体化学计量学来快速适应无关的细胞毒性化合物。这些发现表明，非整倍性是真核生物中应激诱导突变的一种形式，能够促进表型的快速发展和耐药性，并揭示了Hsp90在调节应激条件下适应性状的出现方面的新作用。

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  • 来源
    《Nature》 |2012年第7384期|p.246-250|共5页
  • 作者

    Guangbo Chen; William D. Bradford; Chris W. Seidel; Rong Li;

  • 作者单位

    Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA,Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA;

    Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA;

    Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA,Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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