Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy.
Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy.
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DOI：
10.1038/nature10795
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发表时间：
2012-01-29
期刊：
影响因子：
64.8
通讯作者：
Li, Rong
中科院分区：
文献类型：
--
作者：
Chen, Guangbo;Bradford, William D.;Seidel, Chris W.;Li, Rong
非整倍体，即染色体数目不均的一种状态，是一种具有较大影响的突变形式，能够在多种应激条件下产生适应性表型。在此我们研究多效性应激是否反过来会在出芽酵母中诱导非整倍体。我们发现，尽管多种应激可导致染色体不稳定性（CIN）增加，但由瞬时Hsp90抑制或热激引起的蛋白质毒性应激会使CIN大幅升高，从而产生核型呈嵌合状态的细胞群体。后一种效应与Hsp90伴侣复合物在动粒组装中在进化上保守的作用有关。在Hsp90抑制剂存在的情况下持续生长会导致出现获得了15号染色体的耐药菌落。这种耐药表型是一种数量性状，涉及15号染色体上至少两个基因的拷贝数增加。短期暴露于Hsp90应激通过不同的非整倍体染色体化学计量增强了对不相关的细胞毒性化合物的快速适应。这些发现表明，非整倍体是真核生物中一种应激诱导的突变形式，能够推动快速的表型进化和耐药性，并揭示了Hsp90在调节应激下适应性性状出现方面的新作用。
Aneuploidy, a state of having uneven numbers of chromosomes, is a form of large-effect mutation able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could in turn induce aneuploidy in budding yeast. We show that while diverse stresses can induce an increase in chromosome instability (CIN), proteotoxic stress, caused by transient Hsp90 inhibition or heat-shock, drastically elevated CIN to produce karyotypically mosaic cell population. The latter effect is linked to an evolutionarily conserved role for Hsp90 chaperon complexes in kinetochore assembly. Continued growth in the presence of Hsp90 inhibitor resulted in 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 cyto-toxic compounds through different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fueling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress.
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DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.200910036
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Davies AE;Kaplan KB
通讯作者：
Kaplan KB
影响因子：
8
作者：
Sharma, SV;Agatsuma, T;Nakano, H
通讯作者：
Nakano, H
影响因子：
7.5
作者：
Pavelka N;Rancati G;Li R
通讯作者：
Li R
影响因子：
64.8
作者：
Pavelka, Norman;Rancati, Giulia;Zhu, Jin;Bradford, William D.;Saraf, Anita;Florens, Laurence;Sanderson, Brian W.;Hattem, Gaye L.;Li, Rong
通讯作者：
Li, Rong