Aneuploidy Drives Genomic Instability in Yeast

Sheltzer, Jason M.; Blank, Heidi M.; Pfau, Sarah J.; Tange, Yoshie; George, Benson M.; Humpton, Timothy J.; Brito, Ilana L.; Hiraoka, Yasushi; Niwa, Osami; Amon, Angelika

doi:10.1126/science.1206412

Cited by 376 publications

(382 citation statements)

References 23 publications

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

et al. 2016

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SummaryAneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole, thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age‐associated phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

et al. 2016

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“…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).…”

Section: Aneuploidy Triggers Genomic Instability In Human Cellsmentioning

confidence: 90%

“…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.…”

Section: Aneuploidy Triggers Genomic Instability In Human Cellsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Too much to handle — how gaining chromosomes destabilizes the genome

Passerini

Storchová

2016

Cell Cycle

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Most eukaryotic organisms are diploid, with 2 chromosome sets in their nuclei. Whole chromosomal aneuploidy, a deviation from multiples of the haploid chromosome number, arises from chromosome segregation errors and often has detrimental consequences for cells. In humans, numerical aneuploidy severely impairs embryonic development and the rare survivors develop disorders characterized by multiple pathologies. Moreover, as many as 75 % of malignant tumors display aneuploidy. Although the exact contribution of aneuploidy to tumorigenesis remains unclear, previous studies have suggested that aneuploidy may affect the maintenance of genome integrity. We found that human cells with extra chromosomes showed phenotypes suggestive of replication defects, a phenomenon which we went on to characterize as being due to the aneuploidy-driven downregulation of replication factors, in particular of the replicative helicase MCM2-7. Thus, missegregation of even a single chromosome can further promote genomic instability and thereby contribute to tumor development. In this review we will examine the possible causes of downregulation of replicative factors and discuss the consequences of genomic instability in aneuploid cells.

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Mitosis: Chromosome Segregation and Stability

Mustaly

Ganem

2015

Encyclopedia of Life Sciences

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Mammalian cells are charged with the task of evenly distributing 46 chromosomes to each of two daughter cells during every mitotic cell division. This is achieved by a microtubule‐based cellular structure termed the mitotic spindle. However, numerous cellular and/or genetic defects are known to impair the fidelity of mitosis and promote chromosome segregation errors and aneuploidy. Missegregation of even a single chromosome leads to the deregulated expression of hundreds to thousands of genes, including many that are involved in essential processes such as DNA replication, repair and mitosis. Consequently, while aneuploidy is most typically detrimental to cell viability, it also has the potential to initiate a self‐propagating cycle of chromosome instability that can ultimately promote tumour initiation, progression and relapse. Key Concepts Chromosome segregation is driven by the mitotic spindle. Multiple genetic and/or cell biological defects are known to cause chromosome missegregation and aneuploidy. Aneuploidy is poorly tolerated in normal cells. Cancer cells adapt to tolerate aneuploidy. Cells that persistently missegregate chromosomes are termed chromosomally unstable (CIN). CIN promotes tumour initiation, progression and relapse and correlates with poor patient prognosis. Aneuploidy and CIN are hallmarks of human tumours.

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Aneuploidy Drives Genomic Instability in Yeast

Cited by 376 publications

References 23 publications

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Too much to handle — how gaining chromosomes destabilizes the genome

Mitosis: Chromosome Segregation and Stability

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