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Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

ABSTRACT: 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.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE75623 | GEO | 2015/12/04

SECONDARY ACCESSION(S): PRJNA305028

REPOSITORIES: GEO

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Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

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

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

Ssd1 and Gcn2 suppress global translational efficiency in replicatively aged yeast, while their activation in young cells extends lifespan

Project description:Using ribosome profiling, we find globally reduced translation efficiency during mitotic / replicative aging in budding yeast. Two mechanisms contribute to this: Firstly, the mRNA binding protein Ssd1 is induced during aging, sequestering mRNAs to P-bodies and stress granules that are abundant in old cells. Indeed, overexpression of Ssd1 reduced protein synthesis in young cells and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, the Gcn2 kinase is activated in old cells, phosphorylating and inactivating the translational initiation factor eIF2α. Accordingly, deletion of GCN2 reduced the translational defect of old cells. Furthermore, overexpressing an uncharged tRNA to fully activate Gcn2, or overexpression of its downstream mediator, Gcn4, extended replicative lifespan in a manner that was mostly dependent on autophagy without inhibiting the TOR pathway. As such, Ssd1 induction, activation of the integrated stress response or autophagy are favorable TOR-independent therapeutic targets for lifespan extension.

2018-08-10 | GSE104506 | GEO

Distinct Adaptive Mechanisms Drive Recovery from Aneuploidy Caused by Loss of the Ulp2 SUMO Protease [WGS]

Project description:In response to acute loss of the Ulp2 SUMO-specific protease, yeast become disomic for chromosome I (ChrI) and ChrXII. Here we report that ChrI disomy, which creates an adaptive advantage in part by increasing the dosage of the Ccr4 deadenylase, was eliminated by extended passaging. Loss of aneuploidy is often accompanied by mutations in essential SUMO-ligating enzymes, which reduced polySUMO-conjugate accumulation. The mRNA levels for almost all ribosomal proteins increases transiently upon initial loss of Ulp2, but elevated Ccr4 levels limit excess ribosome formation. Notably, extended passaging leads to increased levels of many small nucleolar RNAs (snoRNAs) involved in ribosome biogenesis, and higher dosage of three linked ChrXII snoRNA genes suppressed ChrXII disomy in ulp2Δ cells. Our data reveal that aneuploidy allows rapid adaptation to Ulp2 loss, but long-term adaptation restores euploidy. Cellular evolution restores homeostasis through countervailing mutations in SUMO-modification pathways and regulatory shifts in ribosome biogenesis.

2018-11-13 | GSE121899 | GEO

Distinct Adaptive Mechanisms Drive Recovery from Aneuploidy Caused by Loss of the Ulp2 SUMO Protease [RNA-seq]

2018-11-13 | GSE121898 | GEO

Multiomics of GCN4-dependent replicative lifespan extension models reveals Gcn4 as a regulator of protein turnover in yeast

Project description:We have shown that multiple tRNA synthetase inhibitors can increase lifespan in both the nematode C. elegans and the budding yeast S. cerevisiae by acting through the conserved transcription factor Gcn4 (yeast) / ATF-4 (worms). To further understand the biology downstream of this conserved transcription factor in the yeast model system, we looked at two different yeast models known to have both upregulated Gcn4, and GCN4-dependent increased replicative lifespan. These two models are rpl31aΔ yeast, and yeast treated with the tRNA synthetase inhibitor borrelidin. We used both proteomic and RNAseq analysis of a block experimental design that included both of these models, to identify GCN4-dependent changes in these two longlived strains of yeast. Proteomic analysis of these yeast indicate that the longlived yeast have increased abundance of proteins involved in amino acid biosynthesis. RNASeq of these same yeast uncovered further regulation of protein turnover, identifying the differential expression of genes associated with both autophagy and with the ubiquitin proteasome system. The data presented here further underscore the important role that GCN4 and its orthologs play in the maintenance of protein homeostasis, which is itself an important hallmark of aging. Importantly, these changes could also have wider-ranging implications in the understanding and treatment of diseases of aging characterized by protein aggregation.

2023-11-11 | GSE242739 | GEO

Loss of the SUMO Protease Ulp2 Triggers a Specific Multi-Chromosome Aneuploidy

Project description:Post-translational protein modification by the small ubiquitin-related modifier (SUMO) protein regulates numerous cellular pathways, including transcription, cell division and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. To investigate changes to the transcriptome of cells lacking Ulp2, whole-genome RNA sequencing (RNA-seq) was employed. Unexpectedly, ulp2Δ cells display a general two-fold increase in transcript levels across two particular chromosomes, Chromosome I (ChrI) and Chromosome XII (ChrXII). Quantification of relative DNA levels showed that ChrI and ChrXII are present at twice their normal copy number in ulp2Δ cells. This double disomy occurs in mutants in multiple genetic backgrounds and does not require passage through meiosis. An abnormal number of chromosomes in a cell, termed aneuploidy, is usually deleterious. However, development of specific aneuploidies allows rapid adaptation to cellular stresses in yeast and other species, and aneuploidy characterizes most tumors. Extra copies of ChrI and ChrXII appear quickly following loss of active Ulp2, suggesting aneuploidy is an adaptive mechanism in cells lacking the functional SUMO protease. The specific aneuploidy in ulp2Δ cells highlights a unique example of a homogeneous, multi-chromosome aneuploidy in response to mutation of a single gene.

2017-08-11 | GSE85501 | GEO

The Genetic Basis of Aneuploidy Tolerance in Wild Yeast

Project description:Aneuploidy, in which cells carry an abnormal chromosome count, is detrimental during development yet common in human cancers; why cells differ in tolerance remains unclear. We mapped the genetic basis of aneuploidy tolerance in wild Saccharomyces cerevisiae versus the sensitive lab strain to Ssd1, an RNA-binding protein involved in translation whose loss recapitulates aneuploidy signatures in laboratory yeast. We find Ssd1 localizes to mitochondria, influences localization of nuclear-encoded mitochondrial mRNAs and/or abundance of the encoded proteins, influences mitochondrial function, and minimizes protein aggregates upon chromosome amplification. Recapitulating ssd1D defects with combinatorial drug treatment selectively targets wild-type aneuploids in multiple strains, suggesting therapeutic approaches. Our work adds to elegant studies done in the sensitized laboratory strain to present a mechanistic understanding of aneuploidy tolerance in eukaryotes.

2020-01-08 | GSE132425 | GEO

Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations or stress responses

Project description:The protein homeostasis (proteostasis) network maintains balanced protein synthesis, folding, transport and degradation within a cell. Because failure to maintain proteostasis is associated with aging and disease, a concerted effort has been placed on studying how the proteostasis network responds to various stresses. Typically, this is accomplished using ectopic overexpression of well-characterized, model misfolded protein substrates; however, how cells tolerate large-scale, diverse burden to the proteostasis network is not understood. Aneuploidy, the state of imbalanced chromosome content, adversely affects the proteostasis network by dysregulating the expression of hundreds of proteins simultaneously. Using aneuploid yeast cells as a model, we address what compensatory adjustments enable cells to tolerate large-scale, diverse challenges to the proteostasis network. Here we show adapted aneuploid Saccharomyces cerevisiae strains that exhibit robust growth and enhanced stress tolerance associated with enhancement of translation, folding, and quality control systems without genetic changes or activation of canonical stress response pathways.

2020-08-17 | GSE140733 | GEO

The expression levels of genes on trisomic chromosomes (chromosome 13, 18 or 21) are increased approximately 1.5-fold on average compared with diploid cells

Project description:Phenotypes in chromosome abnormalities do not arise as a mere summation of the specific effects of dosage-sensitive genes, but as a result of the synergistic actions of whole chromosomes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.

2019-07-18 | GSE120291 | GEO

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