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

Max A.B. Haase, Guðjón Ólafsson, Rachel L. Flores, Emmanuel Boakye-Ansah, Alex Zelter, Miles Sasha Dickinson, Luciana Lazar-Stefanita, David M. Truong, Charles L. Asbury, Trisha N. Davis, Jef D. Boeke

Research output: Contribution to journalArticlepeer-review


Forcing 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.

Original languageEnglish (US)
Article numbere112600
JournalEMBO Journal
Issue number8
StatePublished - Apr 17 2023


  • Saccharomyces cerevisiae
  • aneuploidy
  • centromere dysfunction
  • histones
  • kinetochore

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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