Saccharomyces cerevisiae
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PROVIDER: PRJNA119971 | ENA |
REPOSITORIES: ENA
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Project description:In Saccharomyces cerevisiae, Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events Controlled by the Tel1 and Mec1 Kinases Cancer cells often have elevated frequencies of chromosomal aberrations, and it is likely that loss of genome stability is one driving force behind tumorigenesis. Deficiencies in DNA replication, DNA repair, or cell cycle checkpoints can all contribute to increased rates of chromosomal duplications, deletions and translocations. The Saccharomyces cerevisiae proteins Tel1 and Mec1 (homologues of the human ATM and ATR proteins, respectively) are known to participate in the DNA damage response, replication checkpoint, and telomere maintenance pathways and are critical to maintain genome stability. In the absence of induced DNA damage, tel1 mec1 diploid yeast strains exhibit extremely high rates of chromosome aneuploidy. There is a significant bias towards trisomy of chromosomes II, VIII, X, and XII, whereas the smallest chromosomes I and VI are commonly monosomic. tel1 mec1 strains also demonstrate elevated levels of chromosome rearrangements, including translocations as well as interstitial duplications and deletions. Restoring wild-type telomere length with the Cdc13-Est2 fusion protein substantially reduces the amount of chromosome rearrangements in tel1 mec1 strains. This result suggests that most of the rearrangements are initiated by telomere-telomere fusions. However, the telomere defects associated with tel1 mec1 strains do not cause the high rate of aneuploidy, as restoring proper telomere function does not prevent cells from becoming aneuploid. Our data demonstrate that the same mutant genotype can produce both high levels of chromosome rearrangements and high levels of aneuploidy, and these two types of events occur through separate mechanisms.
2009-09-03 | GSE17903 | GEO
Project description:Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to the cryptic mating type loci but was associated with global changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by increasing the copy number of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.
2017-09-12 | GSE98435 | GEO
Project description:Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to the cryptic mating type loci but was associated with global changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by increasing the copy number of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.
2017-09-12 | GSE98282 | GEO
Project description:Aneuploidy 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.
2015-12-04 | GSE75623 | GEO
Project description:Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, defined as chromosomal instability (CIN). The molecular mechanisms underlying CIN are largely unknown. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage cause chromosomal aberrations at remarkably high frequencies under both selective and non-selective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage results in a “gain of CIN” phenotype and leads to profound karyotypic diversification. These results illustrate a novel mechanism for genome destabilization, which is likely to be relevant to human carcinogenesis. Keywords: CGH-array
2008-02-10 | GSE10152 | GEO
Project description:Aneuploidy has a myriad of consequences for health and disease, yet models of aneuploidy toxicity are still widely debated. To distinguish the effects of specific genes from the generalized burden of chromosome amplification, we measured the effects of duplicating individual genes in euploid cells as well as in select aneuploids using a barcoded plasmid library. We analyzed the responses of cells with and without extra chromosomes, as well as those with and without RNA-binding protein Ssd1. Deletion of Ssd1 sensitizes cells to chromosome amplification, but the source of this vulnerability is not known. Results of this experiment were used to interrogate determinants of aneuploidy toxicity, test models of Ssd1 dependence, and identify vulnerabilities of sensitized (ssd1-) and wild-type aneuploids. We also used the fitness effects of gene duplication in euploid cells to model the cost associated with chromosome duplication.
2024-05-01 | GSE263221 | GEO
Project description:Genomic instability is a common feature found in cancer cells. Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division, and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanism that explains cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient inactivation yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity (LOH), are mainly detected on the rDNA-bearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins and controlling spindle dynamics in a well-defined window within anaphase, we speculate that its transient inactivation causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny.
2015-05-05 | GSE68530 | GEO
Project description:Aneuploidy 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. These are all CGH arrays comparing DNA content between the indicated strain of interest and a wt control.
2015-12-04 | E-GEOD-75623 | biostudies-arrayexpress
Project description:Loss of the SUMO Protease Ulp2 Triggers a Specific Multi-Chromosome Aneuploidy
| PRJNA338670 | ENA