Multiple routes of adaptation to high levels of CIN and aneuploidy in budding yeast

Abstract

Both an increased frequency of chromosome missegregation (chromosomal instability) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. Paradoxically, both chromosomal instability and aneuploidy are also associated with substantial decreases in cellular fitness. 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). The CPC is an essential regulator of chromosome segregation fidelity. We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies. However, targeted mutations of specific genes were notably absent in the short term. 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, members of the SCFCdc4 complex, the mitotic kinase Mps1, and a member of the CPC itself. These mutants function in two distinct ways, as mutations in the outer kinetochore suppress Bir1 deletion indirectly by destabilizing connections between the chromosomes and the mitotic spindle, whereas the other three categories of mutations affect the CPC directly. As a consequence of the accumulation of suppressor point mutations, overall levels of aneuploidy decreased. These experiments demonstrate a timeline of adaptation to high rates of CIN wherein cells first acquire specific aneuploidies that suppress the CIN phenotype, next develop point mutations that more specifically target the source of CIN, and finally reduce the level of aneuploidy to relieve the fitness burden placed by aneuploidy on the cell.

DASH/Dam1 complex mutants stabilize ploidy by weakening kinetochore-microtubule attachments

“…During preparation of our manuscript Clarke et al reported strikingly similar conclusions from a completely orthogonal genetic screen for elevated rates of aneuploidy (Clarke et al, 2022). Notably, they developed a screen for suppressors of deficiency in BIR1, encoding a component of the chromosomal passenger complex, deletion of which leads to increased chromosome segregation defects and elevated aneuploidy.…”

Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies

“…In support of the second hypothesis, we found a mutation in the MPS1 gene specifically in a cell line with a karyotype that was highly divergent from the other adapted populations. Altered aneuploid karyotypes resulting from specific mutations has also recently been reported in yeast (Clarke et al 2022). In conclusion, the ability to recapitulate both general and cell line-specific aneuploidy patterns in human cells is an important step in determining the bases behind these patterns.…”