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Nonsense suppression

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https://www.readbyqxmd.com/read/28188297/alternative-splicing-in-the-cytochrome-p450-superfamily-expands-protein-diversity-to-augment-gene-function-and-redirect-human-drug-metabolism
#1
Andrew J Annalora, Craig B Marcus, Patrick L Iversen
The human genome encodes 57 cytochrome P450 (CYP) genes whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics and unknown numbers of endogenous compounds including steroids, retinoids and icosinoids. Indeed, CYP genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human CYP transcriptome. This review describes a remarkable diversification of the 57 human CYP genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's CYP proteome...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28178277/paucity-of-intact-non-induced-provirus-with-early-long-term-antiretroviral-therapy-of-perinatal-hiv-infection
#2
Kaitlin Rainwater-Lovett, Carrie Ziemniak, Douglas Watson, Katherine Luzuriaga, George Siberry, Ann Petru, YaHui Chen, Priyanka Uprety, Margaret McManus, Ya-Chi Ho, Susanna L Lamers, Deborah Persaud
The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults...
2017: PloS One
https://www.readbyqxmd.com/read/28165652/candidate-susceptibility-variants-for-esophageal-squamous-cell-carcinoma
#3
Iikki Donner, Riku Katainen, Tomas Tanskanen, Eevi Kaasinen, Mervi Aavikko, Kristian Ovaska, Miia Artama, Eero Pukkala, Lauri A Aaltonen
Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life-time risk of ESCC, but no other well-established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth...
February 6, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28145797/characterisation-of-new-generation-aminoglycoside-promoting-premature-termination-codon-readthrough-in-cancer-cells
#4
Laure Bidou, Olivier Bugaud, Valery Belakhov, Timor Baasov, Olivier Namy
Nonsense mutations, generating premature termination codons (PTCs), account for 10% to 30% of the mutations in tumour suppressor genes. Nonsense translational suppression, induced by small molecules including gentamicin and G418, has been suggested as a potential therapy to counteract the deleterious effects of nonsense mutations in several genetic diseases and cancers. We describe here that NB124, a synthetic aminoglycoside derivative recently developed especially for PTC suppression, strongly induces apoptosis in human tumour cells by promoting high level of PTC readthrough...
February 1, 2017: RNA Biology
https://www.readbyqxmd.com/read/28121133/probing-the-structural-mechanism-of-partial-agonism-in-glycine-receptors-using-the-fluorescent-artificial-amino-acid-anap
#5
Ming S Soh, Argel Estrada-Mondragon, Nela Durisic, Angelo Keramidas, Joseph W Lynch
The efficacy of an agonist at a pentameric ligand-gated ion channel is determined by the rate at which it induces a conformational change from the resting closed state to a preopen ("flip") state. If the ability of an agonist to promote this isomerization is sufficiently low, then it becomes a partial agonist. As partial agonists at pentameric ligand-gated ion channels show considerable promise as therapeutics, understanding the structural basis of the resting-flip-state isomerization may provide insight into therapeutic design...
February 2, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28105933/haploid-yeast-cells-undergo-a-reversible-phenotypic-switch-associated-with-chromosome-ii-copy-number
#6
Polina Drozdova, Ludmila Mironova, Galina Zhouravleva
BACKGROUND: SUP35 and SUP45 are essential genes encoding polypeptide chain release factors. However, mutants for these genes may be viable but display pleiotropic phenotypes which include, but are not limited to, nonsense suppressor phenotype due to translation termination defect. [PSI (+)] prion formation is another Sup35p-associated mechanism leading to nonsense suppression through decreased availability of functional Sup35p. [PSI (+)] differs from genuine sup35 mutations by the possibility of its elimination and subsequent re-induction...
December 22, 2016: BMC Genetics
https://www.readbyqxmd.com/read/28096462/unique-contributions-of-an-arginine-side-chain-to-ligand-recognition-in-a-glutamate-gated-chloride-channel
#7
Timothy Lynagh, Vitaly V Komnatnyy, Stephan A Pless
Glutamate recognition by neurotransmitter receptors often relies on arginine (Arg) residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. Using the in vivo nonsense suppression approach, we report the first successful incorporation of the isosteric, titratable Arg analog, canavanine, into a neurotransmitter receptor in a living cell, utilizing a glutamate-gated chloride channel from the nematode Haemonchus contortus...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28077719/suppressing-n-acetyl-l-aspartate-synthesis-prevents-loss-of-neurons-in-a-murine-model-of-canavan-leukodystrophy
#8
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
: Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-l-aspartate (NAA) to acetate and l-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28069571/apc-c-dysfunction-limits-excessive-cancer-chromosomal-instability
#9
Laurent Sansregret, James O Patterson, Sally Dewhurst, Carlos López-García, André Koch, Nicholas McGranahan, William Chong Hang Chao, David J Barry, Andrew Rowan, Rachael Instrell, Stuart Horswell, Michael Way, Michael Howell, Martin R Singleton, René H Medema, Paul Nurse, Mark Petronczki, Charles Swanton
: Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization...
February 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28065590/mechanism-and-evidence-of-nonsense-suppression-therapy-for-genetic-eye-disorders
#10
REVIEW
Rose Richardson, Matthew Smart, Dhani Tracey-White, Andrew R Webster, Mariya Moosajee
Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner...
January 6, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28027311/somatic-mutation-patterns-in-hemizygous-genomic-regions-unveil-purifying-selection-during-tumor-evolution
#11
Jimmy Van den Eynden, Swaraj Basu, Erik Larsson
Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/28027291/interaction-of-prions-causes-heritable-traits-in-saccharomyces-cerevisiae
#12
Anton A Nizhnikov, Tatyana A Ryzhova, Kirill V Volkov, Sergey P Zadorsky, Julia V Sopova, Sergey G Inge-Vechtomov, Alexey P Galkin
The concept of "protein-based inheritance" defines prions as epigenetic determinants that cause several heritable traits in eukaryotic microorganisms, such as Saccharomyces cerevisiae and Podospora anserina. Previously, we discovered a non-chromosomal factor, [NSI+], which possesses the main features of yeast prions, including cytoplasmic infectivity, reversible curability, dominance, and non-Mendelian inheritance in meiosis. This factor causes omnipotent suppression of nonsense mutations in strains of S. cerevisiae bearing a deleted or modified Sup35 N-terminal domain...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/28017590/fluorescence-amplification-method-for-forward-genetic-discovery-of-factors-in-human-mrna-degradation
#13
Andrei Alexandrov, Mei-Di Shu, Joan A Steitz
Nonsense-mediated decay (NMD) degrades mRNAs containing a premature termination codon (PTC). PTCs are a frequent cause of human genetic diseases, and the NMD pathway is known to modulate disease severity. Since partial NMD attenuation can potentially enhance nonsense suppression therapies, better definition of human-specific NMD is required. However, the majority of NMD factors were first discovered in model organisms and then subsequently identified by homology in human. Sensitivity and throughput limitations of existing approaches have hindered systematic forward genetic screening for NMD factors in human cells...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27966891/combining-sense-and-nonsense-codon-reassignment-for-site-selective-protein-modification-with-unnatural-amino-acids
#14
Zhenling Cui, Sergey Mureev, Mark E Polinkovsky, Zakir Tnimov, Zhong Guo, Thomas Durek, Alun Jones, Kirill Alexandrov
Incorporation of unnatural amino acids (uAAs) via codon reassignment is a powerful approach for introducing novel chemical and biological properties to synthesized polypeptides. However, the site-selective incorporation of multiple uAAs into polypeptides is hampered by the limited number of reassignable nonsense codons. This challenge is addressed in the current work by developing Escherichia coli in vitro translation system depleted of specific endogenous tRNAs. The translational activity in this system is dependent on the addition of synthetic tRNAs for the chosen sense codon...
December 30, 2016: ACS Synthetic Biology
https://www.readbyqxmd.com/read/27938668/cellular-encoding-of-cy-dyes-for-single-molecule-imaging
#15
Lilia Leisle, Rahul Chadda, John D Lueck, Daniel T Infield, Jason D Galpin, Venkatramanan Krishnamani, Janice L Robertson, Christopher A Ahern
A general method is described for the site-specific genetic encoding of cyanine dyes as non-canonical amino acids (Cy-ncAAs) into proteins. The approach relies on an improved technique for nonsense suppression with in vitro misacylated orthogonal tRNA. The data show that Cy-ncAAs (based on Cy3 and Cy5) are tolerated by the eukaryotic ribosome in cell-free and whole-cell environments and can be incorporated into soluble and membrane proteins. In the context of the Xenopus laevis oocyte expression system, this technique yields ion channels with encoded Cy-ncAAs that are trafficked to the plasma membrane where they display robust function and distinct fluorescent signals as detected by TIRF microscopy...
December 12, 2016: ELife
https://www.readbyqxmd.com/read/27913587/suppressing-n-acetyl-l-aspartate-naa-synthesis-prevents-loss-of-neurons-in-a-murine-model-of-canavan-leukodystrophy
#16
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-L-aspartate (NAA) to acetate and L-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27905550/deep-sequencing-of-transcriptome-profiling-of-gstm2-knock-down-in-swine-testis-cells
#17
Yuqi Lv, Yi Jin, Yongqiang Zhou, Jianjun Jin, Zhenfa Ma, Zhuqing Ren
Glutathione-S-transferases mu 2 (GSTM2), a kind of important Phase II antioxidant enzyme of eukaryotes, is degraded by nonsense mediated mRNA decay due to a C27T substitution in the fifth exon of pigs. As a reproductive performance-related gene, GSTM2 is involved in embryo implantation, whereas, functional deficiency of GSTM2 induces pre- or post-natal death in piglets potentially. To have some insight into the role of GSTM2 in embryo development, high throughput RNA sequencing is performed using the swine testis cells (ST) with the deletion of GSTM2...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27877110/forward-genetic-screen-in-caenorhabditis-elegans-suggests-f57a10-2-and-acp-4-as-suppressors-of-c9orf72-related-phenotypes
#18
Xin Wang, Limin Hao, Taixiang Saur, Katelyn Joyal, Ying Zhao, Desheng Zhai, Jie Li, Mochtar Pribadi, Giovanni Coppola, Bruce M Cohen, Edgar A Buttner
An abnormally expanded GGGGCC repeat in C9ORF72 is the most frequent causal mutation associated with amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD). Both gain-of-function (gf) and loss-of-function (lf) mechanisms have been involved in C9ORF72 related ALS/FTLD. The gf mechanism of C9ORF72 has been studied in various animal models but not in C. elegans. In the present study, we described mutant C9ORF72 modeling in C. elegans and report the finding of two suppressor genes. We made transgenes containing 9 or 29 repeats of GGGGCC in C9ORF72, driven by either the hsp-16 promoters or the unc-119 promoter...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27875971/therapeutic-suppression-of-nonsense-mutation-an-emerging-target-in-multiple-diseases-and-thrombotic-disorders
#19
Md Asiful Islam, Fahmida Alam, Mohammad Amjad Kamal, Siew Hua Gan, Kah Keng Wong, Teguh Haryo Sasongko
Nonsense mutations contribute to approximately 10-30% of the total human inherited diseases via disruption of protein translation. If any of the three termination codons (UGA, UAG and UAA) emerges prematurely [known as premature termination codon (PTC)] before the natural canonical stop codon, truncated non-functional proteins or proteins with deleterious loss or gain-of-function activities are synthesized, followed by the development of nonsense mutation-mediated diseases. In the past decade, PTC-associated diseases captured much attention in biomedical research, especially as molecular therapeutic targets via nonsense suppression (i...
22, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27874031/harnessing-short-poly-a-binding-protein-interacting-peptides-for-the-suppression-of-nonsense-mediated-mrna-decay
#20
Tobias Fatscher, Niels H Gehring
Nonsense-mediated mRNA decay (NMD) is a cellular process that eliminates messenger RNA (mRNA) substrates with premature translation termination codons (PTCs). In addition, NMD regulates the expression of a number of physiological mRNAs, for example transcripts containing long 3' UTRs. Current models implicate the interaction between cytoplasmic poly(A)-binding protein (PABPC1) and translation termination in NMD. Accordingly, PABPC1 present within close proximity of a termination codon antagonizes NMD. Here, we use reporter mRNAs with different NMD-inducing 3' UTRs to establish a general NMD-inhibiting property of PABPC1...
November 22, 2016: Scientific Reports
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