DASH/Dam1 complex mutants stabilize ploidy in histone‐humanized yeast by weakening kinetochore‐microtubule attachments

• DOI: 10.15252/embj.2022112600
• Publication Date: 2023-01-18T12:28:45Z
• Authors: Max A B Haase; Guðjón Ólafsson; Rachel L Flores; Emmanuel Boakye‐A...; Alex Zelter; Miles Sasha Dicki...; Luciana Lazar‐Ste...; David M Truong; Charles L Asbury; Trisha N Davis; Jef D Boeke
• Keywords: 0301 basic medicine; Saccharomyces cerevisiae Proteins; Ploidies; Cell Cycle Proteins; Articles; Saccharomyces cerevisiae; Aneuploidy; Microtubules; Histones; 03 medical and health sciences; Chromosome Segregation; Humans; Kinetochores; Microtubule-Associated Proteins

AbstractForcing budding yeast to chromatinize their DNA with human histones manifests an abrupt fitness cost. We previously proposed chromosomal aneuploidy and missense mutations as two potential modes of adaptation to histone humanization. Here, we show that aneuploidy in histone‐humanized yeasts is specific to a subset of chromosomes that are defined by their centromeric evolutionary origins but that these aneuploidies are not adaptive. Instead, we find that a set of missense mutations in outer kinetochore proteins drives adaptation to human histones. Furthermore, we characterize the molecular mechanism underlying adaptation in two mutants of the outer kinetochore DASH/Dam1 complex, which reduce aneuploidy by suppression of chromosome instability. Molecular modeling and biochemical experiments show that these two mutants likely disrupt a conserved oligomerization interface thereby weakening microtubule attachments. We propose a model through which weakened microtubule attachments promote increased kinetochore‐microtubule turnover and thus suppress chromosome instability. In sum, our data show how a set of point mutations evolved in histone‐humanized yeasts to counterbalance human histone‐induced chromosomal instability through weakening microtubule interactions, eventually promoting a return to euploidy.