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Aneuploidy

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Angelika Amon – One of the best experts on this subject based on the ideXlab platform.

  • Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells.
    Genes & Development, 2019
    Co-Authors: Christopher M. Brennan, Laura Pontano Vaites, Jonathan N. Wells, Stefano Santaguida, Joao A. Paulo, Zuzana Storchova, J. Wade Harper, Joseph A. Marsh, Angelika Amon
    Abstract:

    Aneuploidy, a condition characterized by chromosome gains and losses, causes reduced fitness and numerous cellular stresses, including increased protein aggregation. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate and that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits.

  • quantitative proteomic analysis reveals posttranslational responses to Aneuploidy in yeast
    eLife, 2014
    Co-Authors: Noah Dephoure, Angelika Amon, Sunyoung Hwang, Ciara Osullivan, Stacie E Dodgson, Steven P Gygi, Eduardo M Torres
    Abstract:

    Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by Aneuploidy are not well characterized. Here, we examined the consequences of Aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel Aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel Aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that Aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms.

  • Aneuploidy causes proteotoxic stress in yeast
    Genes & Development, 2012
    Co-Authors: Ana Oromendia, Stacie E Dodgson, Angelika Amon
    Abstract:

    Gains or losses of entire chromosomes lead to Aneuploidy, a condition tolerated poorly in all eukaryotes analyzed to date. How Aneuploidy affects organismal and cellular physiology is poorly understood. We found that aneuploid budding yeast cells are under proteotoxic stress. Aneuploid strains are prone to aggregation of endogenous proteins as well as of ectopically expressed hard-to-fold proteins such as those containing polyglutamine (polyQ) stretches. Protein aggregate formation in aneuploid yeast strains is likely due to limiting protein quality-control systems, since the proteasome and at least one chaperone family, Hsp90, are compromised in many aneuploid strains. The link between Aneuploidy and the formation and persistence of protein aggregates could have important implications for diseases such as cancer and neurodegeneration.

Richard T Scott – One of the best experts on this subject based on the ideXlab platform.

  • the nature of Aneuploidy with increasing age of the female partner a review of 15 169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening
    Fertility and Sterility, 2014
    Co-Authors: J M Franasiak, Nathan R Treff, E J Forman, K H Hong, M D Werner, K M Upham, Richard T Scott
    Abstract:

    Objective To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic Aneuploidy. Design Retrospective. Setting Academic. Patient(s) Trophectoderm biopsies. Intervention(s) Comprehensive chromosomal screening performed on patients with blastocysts available for biopsy. Main Outcome Measure(s) Evaluation of the impact of maternal age on the prevalence of Aneuploidy, the probability of having no euploid embryos within a cohort, the complexity of Aneuploidy as gauged by the number of aneuploid chromosomes, and the trisomy/monosomy ratio. Result(s) Aneuploidy increased predictably after 26 years of age. A slightly increased prevalence was noted at younger ages, with >40% Aneuploidy in women 23 years and under. The no euploid embryo rate was lowest (2% to 6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44. Among the biopsies with Aneuploidy, 64% involved a single chromosome, 20% two chromosomes, and 16% three chromosomes, with the proportion of more complex Aneuploidy increasing with age. Finally, the trisomy/monosomy ratio approximated 1 and increased minimally with age. Conclusion(s) The lowest risk for embryonic Aneuploidy was between ages 26 and 30. Both younger and older age groups had higher rates of Aneuploidy and an increased risk for more complex aneuploidies. The overall risk did not measurably change after age 43. Trisomies and monosomies are equally prevalent.

  • accurate single cell 24 chromosome Aneuploidy screening using whole genome amplification and single nucleotide polymorphism microarrays
    Fertility and Sterility, 2010
    Co-Authors: Nathan R Treff, Brynn Levy, X Tao, Richard T Scott
    Abstract:

    Objective To develop and validate a whole genome amplification and single nucleotide polymorphism (SNP) microarray protocol for accurate single cell 24 chromosome Aneuploidy screening. Design Prospective, randomized, and blinded study. Setting Academic reproductive medicine center. Patient(s) Multiple euploid and aneuploid cell lines were obtained from a public repository and blastomeres were obtained after biopsy of cleavage stage embryos from 78 patients undergoing IVF. Main Outcome Measure(s) Accuracy of copy number assignment and consistency of individual SNPs, whole chromosomes, and single cell Aneuploidy status were determined. Intervention(s) None. Result(s) Single cells extracted from karyotypically defined cell lines provided 99.2% accuracy for individual SNPs, 99.8% accuracy for whole chromosomes, and 98.6% accuracy when applying a quality control threshold for the overall assignment of Aneuploidy status. The concurrence for more than 80 million SNPs in 335 single blastomeres was 96.5%. Conclusion(s) We have established and validated a SNP microarray-based single cell Aneuploidy screening technology. Clinical validation studies are underway to determine the predictive value of this methodology.

  • snp microarray based 24 chromosome Aneuploidy screening demonstrates that cleavage stage fish poorly predicts Aneuploidy in embryos that develop to morphologically normal blastocysts
    Molecular Human Reproduction, 2010
    Co-Authors: L E Northrop, Nathan R Treff, Brynn Levy, Richard T Scott
    Abstract:

    Although selection of chromosomally normal embryos has the potential to improve outcomes for patients undergoing IVF, the clinical impact of Aneuploidy screening by fluorescence in situ hybridization (FISH) has been controversial. There are many putative explanations including sampling error due to mosaicism, negative impact of biopsy, a lack of comprehensive chromosome screening, the possibility of embryo self-correction and poor predictive value of the technology itself. Direct analysis of the negative predictive value of FISH-based Aneuploidy screening for an embryo’s reproductive potential has not been performed. Although previous studies have found that cleavage-stage FISH is poorly predictive of Aneuploidy in morphologically normal blastocysts, putative explanations have not been investigated. The present study used a single nucleotide polymorphism (SNP) microarray-based 24 chromosome Aneuploidy screening technology to re-evaluate morphologically normal blastocysts that were diagnosed as aneuploid by FISH at the cleavage stage. Mosaicism and preferential segregation of Aneuploidy to the trophectoderm (TE) were evaluated by characterization of multiple sections of the blastocyst. SNP microarray technology also provided the first opportunity to evaluate self-correction mechanisms involving extrusion or duplication of aneuploid chromosomes resulting in uniparental disomy (UPD). Of all blastocysts evaluated (n = 50), 58% were euploid in all sections despite an aneuploid FISH result. Aneuploid blastocysts displayed no evidence of preferential segregation of abnormalities to the TE. In addition, extrusion or duplication of aneuploid chromosomes resulting in UPD did not occur. These findings support the conclusion that cleavage-stage FISH technology is poorly predictive of Aneuploidy in morphologically normal blastocysts.

Robert Benezra – One of the best experts on this subject based on the ideXlab platform.

  • whole chromosome loss and associated breakage fusion bridge cycles transform mouse tetraploid cells
    The EMBO Journal, 2018
    Co-Authors: Rozario Thomas, Robert Benezra, Daniel Henry Marks, Yvette Chin
    Abstract:

    Abstract Whole chromosome gains or losses (Aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of Aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components, but interpretations of these experiments are clouded by the multiple functions of these proteins. Here, we used a Cre recombinase‐mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12, or 14 in tetraploid immortalized murine embryonic fibroblasts. This methodology also involves the generation of a dicentric chromosome intermediate, which subsequently undergoes a series of breakage–fusion–bridge (BFB) cycles. While the aneuploid cells generally display a growth disadvantage in vitro , they grow significantly better in low adherence sphere‐forming conditions and three of the four lines are transformed in vivo , forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo . Thus, these studies demonstrate a causative role for whole chromosome loss and the associated BFB‐mediated instability in tumorigenesis and may shed light on the early consequences of Aneuploidy in mammalian cells.

  • Whole chromosome loss and associated breakage–fusion–bridge cycles transform mouse tetraploid cells
    The EMBO journal, 2017
    Co-Authors: Rozario Thomas, Daniel Henry Marks, Yvette Chin, Robert Benezra
    Abstract:

    Abstract Whole chromosome gains or losses (Aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of Aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components, but interpretations of these experiments are clouded by the multiple functions of these proteins. Here, we used a Cre recombinase‐mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12, or 14 in tetraploid immortalized murine embryonic fibroblasts. This methodology also involves the generation of a dicentric chromosome intermediate, which subsequently undergoes a series of breakage–fusion–bridge (BFB) cycles. While the aneuploid cells generally display a growth disadvantage in vitro , they grow significantly better in low adherence sphere‐forming conditions and three of the four lines are transformed in vivo , forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo . Thus, these studies demonstrate a causative role for whole chromosome loss and the associated BFB‐mediated instability in tumorigenesis and may shed light on the early consequences of Aneuploidy in mammalian cells.

  • Whole chromosome loss in tetraploid cells confers tumorigenic potential in a mouse allograft model
    , 2017
    Co-Authors: Rozario Thomas, Daniel Henry Marks, Yvette Chin, Robert Benezra
    Abstract:

    Whole chromosome gains or losses (Aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of Aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components but interpretations of these experiments are clouded by the multiple functions of these proteins. Here we used a Cre recombinase-mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12 or 14 in tetraploid immortalized murine embryonic fibroblasts. While the aneuploid cells generally display a growth disadvantage in vitro, they grow significantly better in low adherence sphere-forming conditions and 3 of the 4 lines are transformed in vivo, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo. Thus, these studies demonstrate a causative role for whole chromosome loss in tumorigenesis and may shed light on the early consequences of Aneuploidy in mammalian cells.

Eduardo M Torres – One of the best experts on this subject based on the ideXlab platform.

  • quantitative proteomic analysis reveals posttranslational responses to Aneuploidy in yeast
    eLife, 2014
    Co-Authors: Noah Dephoure, Angelika Amon, Sunyoung Hwang, Ciara Osullivan, Stacie E Dodgson, Steven P Gygi, Eduardo M Torres
    Abstract:

    Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by Aneuploidy are not well characterized. Here, we examined the consequences of Aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel Aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel Aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that Aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms.

  • Transcriptional consequences of Aneuploidy
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Jason M. Sheltzer, Maitreya J. Dunham, Eduardo M Torres, Angelika Amon
    Abstract:

    Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of Aneuploidy-induced phenotypes and the consequences of Aneuploidy on cell physphysiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.

  • Identification of Aneuploidy-tolerating mutations
    Cell, 2010
    Co-Authors: Eduardo M Torres, Noah Dephoure, Steven P Gygi, Amudha Panneerselvam, Cheryl M. Tucker, Charles A. Whittaker, Maitreya J. Dunham, Angelika Amon
    Abstract:

    Aneuploidy causes a proliferative disadvantage in all normal 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 improved proliferative abilities. Their molecular characterization revealed strain-specific genetic alterations as well as mutations shared between different aneuploid strains. Among the latter, a loss-of-function mutamutation in the gene encoding the deubiquitinating enzyme Ubp6 improves growth rates in four different aneuploid yeast strains by attenuating the changes in intracellular protein composition caused by Aneuploidy. 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.

David Pellman – One of the best experts on this subject based on the ideXlab platform.

  • Tetraploidy, Aneuploidy and cancer.
    Current opinion in genetics & development, 2007
    Co-Authors: Neil J. Ganem, Zuzana Storchova, David Pellman
    Abstract:

    Aneuploidy is one of the most obvious differences between normal and cancer cells. However, there remains debate over how aneuploid cells arise and whether or not they are a cause or consequence of tumorigenesis. One proposed route to aneuploid cancer cells is through an unstable tetraploid intermediate. Supporting this idea, recent studies demonstrate that tetraploidy promotes chromosomal aberrations and tumorigenesis in vivo. These tetraploid cells can arise by a variety of mechanisms, including mitotic slippage, cytokinesis failure, and viral-induced cell fusion. Furthermore, new studies suggest that there might not be a ploidy-sensing checkpoint that permanently blocks the proliferation of tetraploid cells. Therefore, abnormal division of tetraploid cells might facilitate genetic changes that lead to aneuploid cancers.