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Role of Ssd1 in modulating protein abundance in aneuploid wild yeast

ABSTRACT: We discovered that wild yeast strains can tolerate extra chromosomes, a condition known as aneuploidy, whereas well-studied laboratory strains cannot. Understanding why some cells can tolerate aneuploidy and others cannot could have far-reaching impact, as for example, 85% of solid tumors are aneuploidy and often benefit from extra chromosomes, and thus identifying mechanisms of aneuploidy sensitization could have therapeutic applications.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Evgenia Shishkova

LAB HEAD: Joshua Coon

PROVIDER: PXD013847 | Pride | 2020-01-17

REPOSITORIES: Pride

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			Action	DRS
	20181019_ES_Gaschlab_Chr12aneupl_DELssd1_rep1_inj1.raw	Raw
	20181019_ES_Gaschlab_Chr12aneupl_DELssd1_rep1_inj2.raw	Raw
	20181019_ES_Gaschlab_Chr12aneupl_DELssd1_rep2_inj1.raw	Raw
	20181019_ES_Gaschlab_Chr12aneupl_DELssd1_rep2_inj2.raw	Raw
	20181019_ES_Gaschlab_Chr12aneupl_DELssd1_rep3_inj1.raw	Raw

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Publications

The genetic basis of aneuploidy tolerance in wild yeast.

Hose James J Escalante Leah E LE Clowers Katie J KJ Dutcher H Auguste HA Robinson DeElegant D Bouriakov Venera V Coon Joshua J JJ Shishkova Evgenia E Gasch Audrey P AP

eLife 20200107

Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory s ...[more]

PMID: 31909711

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Mechanisms of Adaptive Evolution of Aneuploid Cells

Project description:Alteration of normal ploidy (aneuploidy) is an important mechanism of evolution of species. It has been linked to a rapid response to stress and is regarded as a hallmark of cancer. While increased genomic instability of aneuploid cells can accelerate genetic diversification and facilitate adaptation, these cells also face the adverse effects of gene imbalance, resulting in fitness cost. Here, to understand the mechanisms through which cells respond to aneuploidy and develop tolerance leading to fitness restoration, we subjected disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution, forcing disomy maintenance with selection markers. We characterized mutations, karyotype alterations and gene expression changes throughout adaptive evolution, and analyzed them to dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates, and endured a diverse array of adaptive events. Despite remarkable diversity of these events, cells tended to evolve towards normal ploidy through both chromosomal DNA loss and changes in gene expression. We identified genes commonly altered during the evolution of disomic strains, and genes recurrently mutated in multiple lines. Our analyses revealed protein translation, amino acid biosynthesis, transcription regulation, stress response, and nucleotide and protein degradation as key pathways for the adaptive response to aneuploidy and identified transcription factors that mediate this response. Together, these findings define cellular strategies that underlie tolerance to aneuploidy.

2018-08-31 | GSE119272 | GEO

Effects of aneuploidy on cellular physiology and cell division in haploid yeast.

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Identification of Aneuploidy-tolerating Mutations

Project description:Aneuploidy causes a proliferative disadvantage in all cells analyzed to date, yet this condition is associated with a disease characterized by unabated proliferative potential, cancer. The mechanisms that allow cancer cells to tolerate the adverse effects of aneuploidy are not known. To probe this question, we identified aneuploid yeast strains with high proliferative abilities and characterized their genetic alterations. We found both strain-specific genetic alterations and mutations shared between different aneuploid strains. One such mutation, a loss of function mutation in the gene encoding the deubiquitinating enzyme UBP6, improves growth rates in four different aneuploid yeast strains. Our data further suggest that deletion of UBP6 attenuates the effects of aneuploidy on cellular protein composition. Our results demonstrate the existence of aneuploidy-tolerating mutations that improve the fitness of multiple different aneuploidies and highlight the importance of ubiquitin-proteasomal degradation in suppressing the adverse effects of aneuploidy. This dataset contains both expression analysis and CGH of yeast strains bearing extra chromosomes. In all cases, the wt euploid strain grown under the same conditions was used as the reference sample. Reference nucleic acid was generally labeled with Cy3, though some were labeled with Cy5 as indicated in the associated annotations for each array. No replicate arrays are included. Expression Samples: GSM513249-GSM513277 CGH Samples: GSM513278-GSM513369

2010-02-24 | E-GEOD-20464 | biostudies-arrayexpress

Effects of aneuploidy on cellular physiology and cell division in haploid yeast.

Project description:Aneuploidy is a condition frequently found in tumor cells but how it affects 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 indicating that they reflect the consequences of additional transcription and translation 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. Keywords: CGH, gene expression This series of microarrays compares yeast strains carrying extra chromosomes to wt yeast with normal chromosome content. Both DNA/CGH and gene expression comparisons were done, as noted. In some experiments, biological replicates were performed as noted. Reference wt nucleic acid was most commonly labeled with Cy3. Experiments labeled as "swap" have the wt reference nucleic acid labeled with Cy5, and ratio values for these experiments are reported as Cy3/Cy5.

2007-05-17 | E-GEOD-7812 | biostudies-arrayexpress

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

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2022-09-19 | MTBLS1612 | MetaboLights

Gene expression profiling of aneuploid IMR90 cells induced by Rb, DNMT1 and MAD2 depletion

Project description:Segregation errors of chromosomes into daughter cells lead to aneuploidy that is considered a major feature of solid tumors. How diploid cells face chromosome mal-segregation and the mechanisms driving aneuploidy tolerance in tumor cells are not yet completely defined. Thus, an important goal in cancer genetics is to identify gene networks leading to aneuploidy as well involved in its tolerance. To this aim we induced aneuploidy in IMR90 human primary cells and analyzed their gene expression profiles by DNA microarrays. Bioinformatics analysis revealed the presence of shared differentially expressed genes, up or down regulated in IMR90 cells after depletion of pRb, DNMT1 and MAD2 all inducing aneuploidy. Normalized data were also analyzed with the Gene Set Enrichment Analysis (GSEA) software to detect deregulated gene-sets associated with the aneuploidy phenotype. GSEA analysis suggested the existence of shared gene-sets/pathways characterizing aneuploidy cells that might be exploited for novel therapeutic approaches in cancer

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