Project description:Aneuploidy severely alters cell physiology and is widespread in cancers and other pathologies. In model cell lines, aneuploidy impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. In this study we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain.
Project description:Aneuploidy severely alters cell physiology and is widespread in cancers and other pathologies. In model cell lines, aneuploidy impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. In this study we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain.
Project description:An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Determining how aneuploidy affects cells is thus critical to understanding tumorigenesis. Here we show that aneuploidy interferes with the degradation of autophagosomes within lysosomes. Mis-folded proteins that accumulate in aneuploid cells due to aneuploidy-induced proteomic changes overwhelm the lysosome with cargo, leading to the observed lysosomal degradation defects. Importantly, aneuploid cells respond to lysosomal saturation. They activate a lysosomal stress pathway that specifically increases the expression of genes needed for autophagy-mediated protein degradation. Our results reveal lysosomal saturation as a universal feature of the aneuploid state that must be overcome during tumorigenesis.
Project description:An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Determining how aneuploidy affects cells is thus critical to understanding tumorigenesis. Here we show that aneuploidy interferes with the degradation of autophagosomes within lysosomes. Mis-folded proteins that accumulate in aneuploid cells due to aneuploidy-induced proteomic changes overwhelm the lysosome with cargo, leading to the observed lysosomal degradation defects. Importantly, aneuploid cells respond to lysosomal saturation. They activate a lysosomal stress pathway that specifically increases the expression of genes needed for autophagy-mediated protein degradation. Our results reveal lysosomal saturation as a universal feature of the aneuploid state that must be overcome during tumorigenesis. RPE-1 cells either untreated or treated with one of Reversine, Bafilomycin A1 or MG132, each condition was done in triplicate. D14-*_Control: untreated control D14-*_Rev: cells treated with 0.5uM Reversine for 24hrs and harvested 48hrs later D14-*_Baf: cells treated with 0.1uM BafA1 for 6hrs D14-*_Mg: cells treated with 1uM MG132 for 24 hrs
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
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.