Aneuploidy Drives Genomic Instability in Yeast

Abstract

Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant growth in cancer.

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).…”

“…First, although we have shown that bul1Δ in the background of chr5 disomy reproduces the lifespan rescue associated with the bul1 Q146K mutation, confirmation of this genotype–phenotype connection could be even further strengthened by reintroducing BUL1 in a chr5 disome bul1Δ background strain and assessing for recurrence of a shortened lifespan. Although theoretically simple, episomal plasmids are difficult to maintain in lifespan experiments and genomic integration into disome strains, which have increased mutation rates (Sheltzer et al ., 2011), could result in additional suppressor mutations, making such an experimental approach fraught. Second, although previous studies have suggested that Bul1 and Bul2 are functionally redundant, we found that bul1Δ alone was sufficient to rescue lifespan in chr5 disomes.…”

Too much to handle — how gaining chromosomes destabilizes the genome

“…6,9 Similarly, studies in yeast showed that whole chromosome aneuploidy leads to increased spontaneous mutagenesis, sensitivity to genotoxic stress and progression through mitosis in the presence of DNA damage. 7,8 Thus, these results indicate that increased s-CIN might be a widespread consequence of the presence of extra chromosome(s).…”

“…12 Haploid yeast strains that carry an additional copy of individual yeast chromosomes show increased rates of chromosome missegregation as well. 7 Thus, whether and how the gain of a single chromosome elevates w-CIN needs to be addressed in a more detailed study and on a broader range of cell lines and karyotypes.…”

“…In support of such a link, aneuploidy often comes hand in hand with whole chromosome instability, elevated spontaneous mutagenesis and sensitivity to genotoxic stress, as it has been shown in yeast model aneuploid strains, and scattered evidence suggests this possibility also in mammalian cells. [6][7][8][9][10][11][12] However, molecular mechanisms that would explain how abnormal chromosome numbers lead to genome rearrangements remain elusive.…”