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

EMBO J. 2023 Apr 17;42(8):e112600. doi: 10.15252/embj.2022112600. Epub 2023 Jan 18.

Abstract

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.

Keywords: Saccharomyces cerevisiae; aneuploidy; centromere dysfunction; histones; kinetochore.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aneuploidy
  • Cell Cycle Proteins / metabolism
  • Chromosome Segregation / genetics
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Kinetochores* / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism
  • Ploidies
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins* / metabolism

Substances

  • Histones
  • Saccharomyces cerevisiae Proteins
  • Microtubule-Associated Proteins
  • Cell Cycle Proteins
  • DAM1 protein, S cerevisiae