Adaptation to high rates of chromosomal instability and aneuploidy through multiple pathways in budding yeast

Abstract

Both an increased frequency of chromosome missegregation (chromosomal instability, CIN) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. To better understand how cells are able to adapt to high levels of chromosomal instability, we previously examined yeast cells that were deleted of the gene BIR1 , a member of the chromosomal passenger complex (CPC). We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies. In this study, we monitored these yeast strains for longer periods of time to determine how cells adapt to high levels of both CIN and aneuploidy in the long term. We identify suppressor mutations that mitigate the chromosome missegregation phenotype. The mutated proteins fall into four main categories: outer kinetochore subunits, the SCF Cdc4 ubiquitin ligase complex, the mitotic kinase Mps1, and the CPC itself. The identified suppressor mutations functioned by reducing chromosomal instability rather than alleviating the negative effects of aneuploidy. Following the accumulation of suppressor point mutations, the number of beneficial aneuploidies decreased. These experiments demonstrate a time line of adaptation to high rates of CIN. image Understanding how yeast cells adapt to high rates of chromosome missegregation should shed light on the tolerance of CIN and aneuploidy in cancer. Here, adaption is shown to proceed via a series of genomic alterations that include the acquisition of specific aneuploidies, karyotype refinement, point mutations, and the eventual loss of beneficial copy number alterations. Yeast cells were adapted to high rates of chromosomal instability for an extended period of time by mutating the chromosomal passenger complex. The adapted strains eventually acquire point mutations that decrease chromosome missegregation rates. These suppressor mutations affect different pathways, some of which directly alter kinetochore‐microtubule interactions. Aneuploid chromosomes that suppress chromosomal instability are lost after the acquisition of point mutations that rescue segregation in a more targeted manner.