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Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy

Abstract

Aneuploidy—the state of having uneven numbers of chromosomes—is a hallmark of cancer1 and a feature identified in yeast from diverse habitats2,3,4,5. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions2,6. 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 assembly7,8. 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.

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Figure 1: Diverse stress conditions, especially Hsp90 inhibition, induce chromosomal instability.
Figure 2: Aneuploidy is the predominant genetic change conferring adaptation to radicicol.
Figure 3: Prior Hsp90 inhibition potentiates adaptation to other stress conditions through divergent aneuploid karyotypes.
Figure 4: Karyotype requirement and dynamics associated with tunicamycin resistance.

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Gene Expression Omnibus

Data deposits

aCGH data are deposited at Gene Expression Omnibus under accession number GSE34087.

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Acknowledgements

We thank N. Pavelka, B. Rubinstein and H. Li for help with data analysis, J. Zhu, B. Fleharty and J. Haug for experimental assistance, S. Lindquist for helpful discussions, and T. Potapova and B. Slaughter for comments on the manuscript. Chromosome fragment strains and Chr XV disomy are gifts from F. Spencer and A. Amon, respectively. This work was supported by National Institutes of Health grant RO1GM059964 to R.L.

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G.C. and R.L. designed and G.C. performed the experiments. W.D.B performed qPCR karyotyping. C.W.S. performed aCGH data analysis. G.C. and R.L. prepared the manuscript. R.L. conceived and supervised the project. All authors read and agreed with the content of the paper.

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Correspondence to Rong Li.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-11 with legends, Supplementary Methods, Supplementary References and Supplementary Tables 1-3. (PDF 2542 kb)

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Chen, G., Bradford, W., Seidel, C. et al. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482, 246–250 (2012). https://doi.org/10.1038/nature10795

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