Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast

Abstract

Aneuploidy is a condition frequently found in tumor cells, but its effect on cellular physiology is not known. We have characterized one aspect of aneuploidy: the gain of extra chromosomes. We created a collection of haploid yeast strains that each bear an extra copy of one or more of almost all of the yeast chromosomes. Their characterization revealed that aneuploid strains share a number of phenotypes, including defects in cell cycle progression, increased glucose uptake, and increased sensitivity to conditions interfering with protein synthesis and protein folding. These phenotypes were observed only in strains carrying additional yeast genes, which indicates that they reflect the consequences of additional protein production as well as the resulting imbalances in cellular protein composition. We conclude that aneuploidy causes not only a proliferative disadvantage but also a set of phenotypes that is independent of the identity of the individual extra chromosomes.

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

“…To investigate a causative relationship between aneuploidy and aging, we measured the replicative lifespans (RLS) of a set of previously well‐characterized disomic yeast strains (‘disomes’): haploid cells, each carrying an extra copy of one of 13 of 16 native yeast chromosomes (Table S1) (Torres et al ., 2007, 2010; Sheltzer et al ., 2011; Oromendia et al ., 2012; Dephoure et al ., 2014). We determined the RLS for each disome using the gold standard method of manually separating daughter cells as they bud from a single mother cell and counting the number of buds produced before a mother cell ceases to divide (Steffen et al ., 2009).…”

“…These YACs are similar in size to native yeast chromosomes but due to the different genetic density of mammalian genomes compared to S. cerevisiae , and the lack of appropriate splicing machinery in yeast, many fewer transcripts and proteins are likely expressed from YACs. Furthermore, previous comparisons between these disomes and YAC strains showed that the YAC strains did not suffer from the proteotoxic stress commonly experienced by disomes (Torres et al ., 2007, 2010; Oromendia et al ., 2012; Dephoure et al ., 2014). Similarly, we found that while the disomes were short lived, strains carrying YACs even as large as 1.6 megabases had lifespans that were similar to wild‐type (Fig.…”

“…All the disomes used in this study were previously shown to have a fitness deficit, as reflected in a lengthened doubling time and other phenotypes, compared to a euploid control (Torres et al ., 2007). Previously, laboratory evolution of each disome selected for evolved clones with a rescued doubling time (Torres et al ., 2010).…”

“…Previous characterization of the disome strains used in this study showed that these strains suffer from proteotoxic stress due to the uncompensated expression of proteins from the disomic chromosome (Torres et al ., 2007, 2010; Oromendia et al ., 2012; Dephoure et al ., 2014). Specifically, the disome strains share an RNA expression profile similar to the environmental stress response and have an increased sensitivity to proteasome‐inhibiting drugs (Torres et al ., 2007).…”

“…While it is often proposed that the correlation between age and aneuploidy is due to increased rates of chromosomal missegregation in older cells, it is possible that the relationship is more complex and that aneuploidy itself contributes to aging phenotypes. Similar to old cells, aneuploid cells suffer from disrupted protein homeostasis due to uncompensated protein expression from the chromosome at altered copy number (Torres et al ., 2007, 2010; Dephoure et al ., 2014) and have increased levels of protein aggregates (Oromendia et al ., 2012). Aneuploidy is further connected to aging by work in mice studying the effects of somatic aneuploidy on aging phenotypes.…”