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Synthetic Lethality Induced by a Strong Drosophila Enhancer of Expanded Polyglutamine Tract  [PDF]
Ping Zhang, Qiming Wang, Hannah Hughes, Gino Intrieri
Open Journal of Genetics (OJGen) , 2014, DOI: 10.4236/ojgen.2014.44028
Abstract:

Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used in an eye-based model to study human neurodegenerative diseases. This system has facilitated the isolation and characterization of abundant Drosophilagenes that interact with the expanded polyglutamine proteins. We used the GMR-Gal4/UAS system to express three proteins containing an expanded polyglutamine tract, or an expanded polyglutamine tract alone. Doubling the dose of these proteins resulted in pupal lethality, indicating that these toxic proteins induced a sensitized condition that is prone to synthetic lethality. By using the GMR-Gal4/UAS system, we showed that a Drosophilagene interacts with three expanded polyglutamine proteins to induce a synthetic lethal phenotype. We further demonstrated that the synthetic lethality was mediated through the toxic expanded polyglutamine tract. Our study raises a possibility that conventional genetic screens may not recover synthetic lethal alleles, which are presumably stronger interacting alleles than the currently known modifiers of an expanded polyglutamine tract, due to synthetic lethality.

Modeling synthetic lethality
Nolwenn Le Meur, Robert Gentleman
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-9-r135
Abstract: In Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products.Modeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions.Two genes are said to be synthetic lethal if mutation of either alone leaves the cell viable, while simultaneous mutation leads to death. In this case, we say that one gene buffers the effect of changes in the other, that is, compensates for the effect of its deletion. The implications of synthetic lethal screening have already been discussed in the context of anticancer therapies and drug development in general [1,2]. Indeed, synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. Although several cellular processes might give rise to synthetic lethality, none are yet well understood. Kaelin [1] proposed that synthetic lethality in loss-of-function alleles can arise from at least four different mechanisms (Figure 1). The cellular organizational units might be uniquely redundant and their roles are essential (type A; direct surrogacy), subunits of an essential multi-protein complex (type B), interconnected components in an essential linear pathway (type C), or they might participate in parallel pathways that are together essential (type D).In Saccharomyces cerevisiae, previous analyses of synthetic genetic datasets have mainly rel
Proinflammatory Mediators of Toxic Shock and Their Correlation to Lethality  [PDF]
Teresa Krakauer,Marilyn J. Buckley,Diana Fisher
Mediators of Inflammation , 2010, DOI: 10.1155/2010/517594
Abstract: Bacterial exotoxins and endotoxins both stimulate proinflammatory mediators but the contribution of each individual toxin in the release of mediators causing lethal shock is incompletely understood. This study examines the cytokine response and lethality of mice exposed to varying doses of staphylococcal enterotoxin B (SEB) or lipopolysaccharide (LPS) and their combinations. In vivo, SEB alone induced moderate levels of IL-2 and MCP-1 and all mice survived even with a high dose of SEB (100 g/mouse). LPS (80 g/mouse) caused 48% lethality and induced high levels of IL-6 and MCP-1. SEB induced low levels of TNF , IL-1, IFN , MIP-2, and LPS synergized with SEB in the expression of these cytokines and that of IL-6 and MCP-1. Importantly, the synergistic action of SEB and LPS resulted in lethal shock and hypothermia. ANOVA of cytokine levels by survival status of SEB-plus-LPS groups revealed significantly higher levels of TNF , IL-6, MIP-2, and MCP-1 in nonsurvivors measured at 8 hours. Significantly higher levels of IFN and IL-2 were observed at 21 hours in nonsurvivors of toxic shock compared to those in survivors. Overall, synergistic action of SEB and LPS resulted in higher and prolonged levels of these key cytokines leading to toxic shock. 1. Introduction Bacterial exotoxins and endotoxins are among the most common etiological agents that cause septic shock [1–3]. Although similar cytokines are released from host cells stimulated with these structurally distinct bacterial products, the stimulants act through distinct cell surface receptors on host cells. Staphylococcal enterotoxin B (SEB) and structurally related exotoxins are bacterial superantigens that potently activate antigen-presenting cells by binding directly to major histocompatibility complex (MHC) class II molecules [1, 4, 5]. These exotoxins also interact with specific Vβ regions of the T cell antigen receptors resulting in polyclonal T cell activation [6]. Interactions of superantigens with antigen-presenting cells and T cells lead to massive proinflammatory cytokine and chemokine release, causing clinical symptoms that include fever, hypotension, and shock [1, 2, 4, 7, 8]. In contrast, lipopolysaccharide (LPS) from gram-negative bacteria binds to a different receptor on monocytes/macrophages. An LPS-binding protein in serum first binds to LPS and facilitates its binding to cell surface protein CD14 on monocytes/macrophages and other cells [9, 10]. The subsequent interaction of LPS/CD14 complex with Toll-like receptor 4 on these cells initiates recruitment of intracellular adaptors and
Lethality and synthetic lethality in the genome-wide metabolic network of Escherichia coli  [PDF]
C. -M. Ghim,K. -I. Goh,B. Kahng
Quantitative Biology , 2004,
Abstract: Recent genomic analyses on the cellular metabolic network show that reaction flux across enzymes are diverse and exhibit power-law behavior in its distribution. While one may guess that the reactions with larger fluxes are more likely to be lethal under the blockade of its catalyzing gene products or gene knockouts, we find, by in silico flux analysis, that the lethality rarely has correlations with the flux level owing to the widespread backup pathways innate in the genome-wide metabolism of \textit{Escherichia coli}. Lethal reactions, of which the deletion generates cascading failure of following reactions up to the biomass reaction, are identified in terms of the Boolean network scheme as well as the flux balance analysis. The avalanche size of a reaction, defined as the number of subsequently blocked reactions after its removal, turns out to be a useful measure of lethality. As a means to elucidate phenotypic robustness to a single deletion, we investigate synthetic lethality in reaction level, where simultaneous deletion of a pair of nonlethal reactions leads to the failure of the biomass reaction. Synthetic lethals identified via flux balance and Boolean scheme are consistently shown to act in parallel pathways, working in such a way that the backup machinery is compromised.
The Role of Protein Interactions in Mediating Essentiality and Synthetic Lethality  [PDF]
David Talavera, David L. Robertson, Simon C. Lovell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062866
Abstract: Genes are characterized as essential if their knockout is associated with a lethal phenotype, and these “essential genes” play a central role in biological function. In addition, some genes are only essential when deleted in pairs, a phenomenon known as synthetic lethality. Here we consider genes displaying synthetic lethality as “essential pairs” of genes, and analyze the properties of yeast essential genes and synthetic lethal pairs together. As gene duplication initially produces an identical pair or sets of genes, it is often invoked as an explanation for synthetic lethality. However, we find that duplication explains only a minority of cases of synthetic lethality. Similarly, disruption of metabolic pathways leads to relatively few examples of synthetic lethality. By contrast, the vast majority of synthetic lethal gene pairs code for proteins with related functions that share interaction partners. We also find that essential genes and synthetic lethal pairs cluster in the protein-protein interaction network. These results suggest that synthetic lethality is strongly dependent on the formation of protein-protein interactions. Compensation by duplicates does not usually occur mainly because the genes involved are recent duplicates, but is more commonly due to functional similarity that permits preservation of essential protein complexes. This unified view, combining genes that are individually essential with those that form essential pairs, suggests that essentiality is a feature of physical interactions between proteins protein-protein interactions, rather than being inherent in gene and protein products themselves.
Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators  [PDF]
Jessica L. McLellan equal contributor,Nigel J. O'Neil equal contributor,Irene Barrett,Elizabeth Ferree,Derek M. van Pel,Kevin Ushey,Payal Sipahimalani,Jennifer Bryan,Ann M. Rose,Philip Hieter
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002574
Abstract: Synthetic lethality has been proposed as a way to leverage the genetic differences found in tumor cells to affect their selective killing. Cohesins, which tether sister chromatids together until anaphase onset, are mutated in a variety of tumor types. The elucidation of synthetic lethal interactions with cohesin mutants therefore identifies potential therapeutic targets. We used a cross-species approach to identify robust negative genetic interactions with cohesin mutants. Utilizing essential and non-essential mutant synthetic genetic arrays in Saccharomyces cerevisiae, we screened genome-wide for genetic interactions with hypomorphic mutations in cohesin genes. A somatic cell proliferation assay in Caenorhabditis elegans demonstrated that the majority of interactions were conserved. Analysis of the interactions found that cohesin mutants require the function of genes that mediate replication fork progression. Conservation of these interactions between replication fork mediators and cohesin in both yeast and C. elegans prompted us to test whether other replication fork mediators not found in the yeast were required for viability in cohesin mutants. PARP1 has roles in the DNA damage response but also in the restart of stalled replication forks. We found that a hypomorphic allele of the C. elegans SMC1 orthologue, him-1(e879), genetically interacted with mutations in the orthologues of PAR metabolism genes resulting in a reduced brood size and somatic cell defects. We then demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. This work demonstrates that large-scale genetic interaction screening in yeast can identify clinically relevant genetic interactions and suggests that PARP inhibitors, which are currently undergoing clinical trials as a treatment of homologous recombination-deficient cancers, may be effective in treating cancers that harbor cohesin mutations.
Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism  [PDF]
Jong-Min Lee,Elena V Ivanova,Ihn Sik Seong,Tanya Cashorali,Isaac Kohane,James F Gusella,Marcy E MacDonald
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030135
Abstract: The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over ~37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1α expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdhQ111/Q111 cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1α-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdhQ111/Q111 cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-κB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD.
ZMIZ1 Preferably Enhances the Transcriptional Activity of Androgen Receptor with Short Polyglutamine Tract  [PDF]
Xiaomeng Li, Chunfang Zhu, William H. Tu, Nanyang Yang, Hui Qin, Zijie Sun
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025040
Abstract: The androgen receptor (AR) is a ligand-induced transcription factor and contains the polyglutamine (polyQ) tracts within its N-terminal transactivation domain. The length of polyQ tracts has been suggested to alter AR transcriptional activity in prostate cancer along with other endocrine and neurologic disorders. Here, we assessed the role of ZMIZ1, an AR co-activator, in regulating the activity of the AR with different lengths of polyQ tracts as ARQ9, ARQ24, and ARQ35 in prostate cancer cells. ZMIZ1, but not ZMIZ2 or ARA70, preferably augments ARQ9 induced androgen-dependent transcription on three different androgen-inducible promoter/reporter vectors. A strong protein-protein interaction between ZMIZ1 and ARQ9 proteins was shown by immunoprecipitation assays. In the presence of ZMIZ1, the N and C-terminal interaction of the ARQ9 was more pronounced than ARQ24 and ARQ35. Both Brg1 and BAF57, the components of SWI/SNF complexes, were shown to be involved in the enhancement of ZMIZ1 on AR activity. Using the chromatin immunoprecipitation assays (ChIP), we further demonstrated a strong recruitment of ZMIZ1 by ARQ9 on the promoter of the prostate specific antigen (PSA) gene. These results demonstrate a novel regulatory role of ZMIZ1 in modulating the polyQ tract length of AR in prostate cancer cells.
Essential Plasticity and Redundancy of Metabolism Unveiled by Synthetic Lethality Analysis  [PDF]
Oriol Güell ,Francesc Sagués ,M. ángeles Serrano
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003637
Abstract: We unravel how functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks. We perform an exhaustive computational screening of synthetic lethal reaction pairs in Escherichia coli in a minimal medium and we find that synthetic lethal pairs divide in two different groups depending on whether the synthetic lethal interaction works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. In E. coli, the analysis of pathways entanglement through essential redundancy supports the view that synthetic lethality affects preferentially a single function or pathway. In contrast, essential plasticity, the dominant class, tends to be inter-pathway but strongly localized and unveils Cell Envelope Biosynthesis as an essential backup for Membrane Lipid Metabolism. When comparing E. coli and Mycoplasma pneumoniae, we find that the metabolic networks of the two organisms exhibit a large difference in the relative importance of plasticity and redundancy which is consistent with the conjecture that plasticity is a sophisticated mechanism that requires a complex organization. Finally, coessential reaction pairs are explored in different environmental conditions to uncover the interplay between the two mechanisms. We find that synthetic lethal interactions and their classification in plasticity and redundancy are basically insensitive to medium composition, and are highly conserved even when the environment is enriched with nonessential compounds or overconstrained to decrease maximum biomass formation.
Essential plasticity and redundancy of metabolism unveiled by synthetic lethality analysis  [PDF]
Oriol Güell,Francesc Sagués,M. ángeles Serrano
Quantitative Biology , 2013, DOI: 10.1371/journal.pcbi.1003637
Abstract: We unravel how functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks. We perform an exhaustive computational screening of synthetic lethal reaction pairs in Escherichia coli in a minimal medium and we find that synthetic lethal pairs divide in two different groups depending on whether the synthetic lethal interaction works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. In E. coli, the analysis of pathways entanglement through essential redundancy supports the view that synthetic lethality affects preferentially a single function or pathway. In contrast, essential plasticity, the dominant class, tends to be inter-pathway but strongly localized and unveils Cell Envelope Biosynthesis as an essential backup for Membrane Lipid Metabolism. When comparing E. coli and Mycoplasma pneumoniae, we find that the metabolic networks of the two organisms exhibit a large difference in the relative importance of plasticity and redundancy which is consistent with the conjecture that plasticity is a sophisticated mechanism that requires a complex organization. Finally, coessential reaction pairs are explored in different environmental conditions to uncover the interplay between the two mechanisms. We find that synthetic lethal interactions and their classification in plasticity and redundancy are basically insensitive to medium composition, and are highly conserved even when the environment is enriched with nonessential compounds or overconstrained to decrease maximum biomass formation.
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