DASH/Dam1 complex mutants stabilize ploidy in histone‐humanized yeast by weakening kinetochore‐microtubule attachments. (18th January 2023)

• Record Type: Journal Article
• Authors: Haase, Max A B; Ólafsson, Guðjón; Flores, Rachel L; Boakye‐Ansah, Emmanuel; Zelter, Alex; Dickinson, Miles Sasha; Lazar‐Stefanita, Luciana; Truong, David M; Asbury, Charles L; Davis, Trisha N; Boeke, Jef D
• Is Part Of: EMBO journal. Volume 42:Number 8(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-18
• Subjects: aneuploidy -- centromere dysfunction -- histones -- kinetochore -- Saccharomyces cerevisiae; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022112600
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Chromosome segregation relies on proper centromere‐kinetochore attachments to microtubules. This study shows that centromere/kinetochore dysfunction in yeast, caused by chromatinization with human histones, is rescued by DASH/Dam1c mutants that reduce the strength of kinetochore‐microtubule attachments. Histone humanization in yeast leads to centromere dysfunction, kinetochore declustering, and persistent aneuploidy. Alteration‐of‐function DASH/Dam1c mutants are adaptive to yeast with human chromatin. DASH/Dam1c mutants stabilize ploidy levels in histone‐humanized yeast. Ploidy stabilization is achieved by disrupting DASH/Dam1c oligomerization thereby weakening microtubule attachments. Abstract : Increased kinetochore‐microtubule turnover suppresses chromosome segregation defects caused by budding yeast chromatinization with human histones.