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Chernoff, Yury O.

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Now showing 1 - 10 of 13
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    Nonhuman Present: Science and Fiction
    ( 2015-10-30) Khapaeva, Dina ; Senf, Carol ; Kemp, Charles C. ; Chernoff, Yury O. ; Yaszek, Lisa
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    Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast
    (Georgia Institute of Technology, 2012-04-19) Gong, He ; Romanova, Nina V. ; Allen, Kim D. ; Chandramowlishwaran, Pavithra ; Gokhale, Kavita ; Newnam, Gary P. ; Mieczkowski, Piotr ; Sherman, Michael Y. ; Chernoff, Yury O.
    Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington’s disease. Fragments of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamine cytotoxicity in cells containing only the prion form of Rnq1 protein. Here we show that expanded polyglutamines both with (poly-QP) or without (poly-Q) a P-rich stretch remain toxic in the presence of the prion form of translation termination (release) factor Sup35 (eRF3). A Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into aggregates counteracts cytotoxicity, suggesting that toxicity is due to Sup35 sequestration. Increase in the levels of another release factor, Sup45 (eRF1), due to either disomy by chromosome II containing the SUP45 gene or to introduction of the SUP45- bearing plasmid counteracts poly-Q or poly-QP toxicity in the presence of the Sup35 prion. Protein analysis confirms that polyglutamines alter aggregation patterns of Sup35 and promote aggregation of Sup45, while excess Sup45 counteracts these effects. Our data show that one and the same mode of polyglutamine aggregation could be cytoprotective or cytotoxic, depending on the composition of other aggregates in a eukaryotic cell, and demonstrate that other aggregates expand the range of proteins that are susceptible to sequestration by polyglutamines.
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    Yeast model for studying heritable mammalian prion disease
    (Georgia Institute of Technology, 2011-12-01) Chernoff, Yury O.
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    Destabilization and recovery of a yeast prion after mild heat shock
    (Georgia Institute of Technology, 2011-05-06) Newnam, Gary P. ; Birchmore, Jennifer L. ; Chernoff, Yury O.
    Yeast prion [PSI+] is a self-perpetuating amyloid of the translational termination factor Sup35. Although [PSI+] propagation is modulated by heat shock proteins (Hsps), high temperature was previously reported to have little or no effect on [PSI+]. Our results show that short-term exposure of exponentially growing yeast culture to mild heat shock, followed by immediate resumption of growth, leads to [PSI+] destabilization, sometimes persisting for several cell divisions after heat shock. Prion loss occurring in the first division after heat shock is preferentially detected in a daughter cell, indicating the impairment of prion segregation that results in asymmetric prion distribution between a mother cell and a bud. Longer heat shock or prolonged incubation in the absence of nutrients after heat shock lead to [PSI+] recovery. Both prion destabilization and recovery during heat shock depend on protein synthesis. Maximal prion destabilization coincides with maximal imbalance between Hsp104 and other Hsps such as Hsp70-Ssa. Deletions of individual SSA genes increase prion destabilization and/or counteract recovery. Dynamics of prion aggregation during destabilization and recovery is consistent with the notion that efficient prion fragmentation and segregation require a proper balance between Hsp104 and other (e. g. Hsp70- Ssa) chaperones. In contrast to heat shock, [PSI+] destabilization by osmotic stressors does not always depend on cell proliferation and/or protein synthesis, indicating that different stresses may impact the prion via different mechanisms. Our data demonstrate that heat stress causes asymmetric prion distribution in a cell division, and confirm that effects of Hsps on prions are physiologically relevant.
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    Arra: genetic study of the yeast prion-interacting proteins
    (Georgia Institute of Technology, 2011-02-28) Chernoff, Yury O.
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    Identification of genes influencing synthetic lethality of genetic and epigenetic alterations in translation termination factors in yeast
    (Georgia Institute of Technology, 2011) Kiktev, D. A. ; Chernoff, Yury O. ; Archipenko, A. V. ; Zhouravleva, G. A.
    Translation termination in eukaryotic cells is determined by proteins Sup35 (eRF3) and Sup45 (eRF1) [1], which interact with a large number of partners [2]. In yeast Saccharomyces cerevisiae, protein Sup35 can form an aggregating epigenetically inherited conformer (prion) [PSI+] [3]. This prion is carried through the cytoplasm and causes disturbances in translation termination, which are phenotypically identified as the dominant omnipotent nonsense suppression. [PSI+] variants with different properties (nonsense suppression efficiency and transmission stability in mitosis) can be obtained in the same yeast strain. The presence of prion [PSI+] leads to lethality in the haploid yeast strain carrying mutations in the gene encoding another termination factor, Sup45 [4]. We have shown that the combination in the diploid strain of some mutant alleles of the SUP45 gene in the heterozygous state with prion [PSI+] entails the death of the hybrid [5]. The synthetic lethality of prion [PSI+] and mutant allele of the sup45 gene depends both on the type of mutant allele and the prion variant. Variant [PSI+], which is a strong suppressor (“strong” [PSI+], or [PSI+]S), causes synthetic lethality with all nonsense mutations and some missense mutations sup45 in the heterozygote. Our data indicate that the lethality of hybrids is correlated with a decreased activity of the Sup45 protein in the cell in case of sup45 mutations. This paper describes a test system that allows identification of proteins that affect the stability of prion [PSI+] and/or the efficiency of translation termination by their effect on the synthetic lethality of the prion conformer Sup35 and mutant alleles of SUP45. This test system is suitable to search for proteins that affect the translation termination efficiency and/ or prion maintenance in yeast cells. Gene library screening using this test system allowed us to identify the CUR1 gene, whose influence on another prion, [URE3], was shown earlier but the effect on translation termination factors was not known.
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    Pathogenic Polyglutamine Tracts Are Potent Inducers of Spontaneous Sup35 and Rnq1 Amyloidogenesis
    (Georgia Institute of Technology, 2010-03-10) Goehler, Heike ; Dröge, Anja ; Lurz, Rudi ; Schnoegl, Sigrid ; Chernoff, Yury O. ; Wanker, Erich E.
    The glutamine/asparagine (Q/N)-rich yeast prion protein Sup35 has a low intrinsic propensity to spontaneously self-assemble into ordered, β-sheet-rich amyloid fibrils. In yeast cells, de novo formation of Sup35 aggregates is greatly facilitated by high protein concentrations and the presence of preformed Q/N-rich protein aggregates that template Sup35 polymerization. Here, we have investigated whether aggregation-promoting polyglutamine (polyQ) tracts can stimulate the de novo formation of ordered Sup35 protein aggregates in the absence of Q/N-rich yeast prions. Fusion proteins with polyQ tracts of different lengths were produced and their ability to spontaneously self-assemble into amlyloid structures was analyzed using in vitro and in vivo model systems. We found that Sup35 fusions with pathogenic (≥54 glutamines), as opposed to non-pathogenic (19 glutamines) polyQ tracts efficiently form seeding-competent protein aggregates. Strikingly, polyQ-mediated de novo assembly of Sup35 protein aggregates in yeast cells was independent of pre-existing Q/N-rich protein aggregates. This indicates that increasing the content of aggregation-promoting sequences enhances the tendency of Sup35 to spontaneously self-assemble into insoluble protein aggregates. A similar result was obtained when pathogenic polyQ tracts were linked to the yeast prion protein Rnq1, demonstrating that polyQ sequences are generic inducers of amyloidogenesis. In conclusion, long polyQ sequences are powerful molecular tools that allow the efficient production of seeding-competent amyloid structures.
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    Yeast models for prion and amyloid diseases
    (Georgia Institute of Technology, 2009-06-15) Chernoff, Yury O.
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    Gene prediction in novel fungal genomes using an ab initio algorithm with unsupervised training
    (Georgia Institute of Technology, 2008-12) Ter-Hovhannisyan,Vardges ; Lomsadze, Alexandre ; Chernoff, Yury O. ; Borodovsky, Mark
    We describe a new ab initio algorithm, GeneMark-ES version 2, that identifies protein-coding genes in fungal genomes. The algorithm does not require a predetermined training set to estimate parameters of the underlying hidden Markov model (HMM). Instead, the anonymous genomic sequence in question is used as an input for iterative unsupervised training. The algorithm extends our previously developed method tested on genomes of Arabidopsis thaliana, Caenorhabditis elegans, and Drosophila melanogaster. To better reflect features of fungal gene organization, we enhanced the intron submodel to accommodate sequences with and without branch point sites. This design enables the algorithm to work equally well for species with the kinds of variations in splicing mechanisms seen in the fungal phyla Ascomycota, Basidiomycota, and Zygomycota. Upon self-training, the intron submodel switches on in several steps to reach its full complexity. We demonstrate that the algorithm accuracy, both at the exon and the whole gene level, is favorably compared to the accuracy of gene finders that employ supervised training. Application of the new method to known fungal genomes indicates substantial improvement over existing annotations. By eliminating the effort necessary to build comprehensive training sets, the new algorithm can streamline and accelerate the process of annotation in a large number of fungal genome sequencing projects
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    Phenotypic detection of mouse PrP aggregation in yeast
    (Georgia Institute of Technology, 2008-03-31) Chernoff, Yury O.