Hsp90 Stress Potentiates Rapid Cellular Adaptation through Induction of Aneuploidy

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(1,2). 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(3,4). 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.