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nonsense-mediated decay

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https://www.readbyqxmd.com/read/28209632/high-resolution-profiling-of-nmd-targets-in-yeast-reveals-translational-fidelity-as-a-basis-for-substrate-selection
#1
Alper Celik, Richard Baker, Feng He, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) plays an important role in eukaryotic gene expression yet the scope and the defining features of NMD-targeted transcripts remain elusive. To address these issues, we re-evaluated the genome-wide expression of annotated transcripts in yeast cells harboring deletions of the UPF1, UPF2, or UPF3 genes. Our new RNA-Seq analyses confirm previous results of microarray studies, but also uncover hundreds of new NMD-regulated transcripts that had escaped previous detection, including many intron-containing pre-mRNAs and several non-coding RNAs...
February 16, 2017: RNA
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
#2
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/28186996/harnessing-rna-sequencing-for-global-unbiased-evaluation-of-two-new-adjuvants-for-dendritic-cell-immunotherapy
#3
Till S M Mathan, Johannes Textor, Annette E Sköld, Inge Reinieren-Beeren, Tom van Oorschot, Mareke Brüning, Carl G Figdor, Sonja I Buschow, Ghaith Bakdash, I Jolanda M de Vries
Effective stimulation of immune cells is crucial for the success of cancer immunotherapies. Current approaches to evaluate the efficiency of stimuli are mainly defined by known flow cytometry-based cell activation or cell maturation markers. This method however does not give a complete overview of the achieved activation state and may leave important side effects unnoticed. Here, we used an unbiased RNA sequencing (RNA-seq)-based approach to compare the capacity of four clinical-grade dendritic cell (DC) activation stimuli used to prepare DC-vaccines composed of various types of DC subsets; the already clinically applied GM-CSF and Frühsommer meningoencephalitis (FSME) prophylactic vaccine and the novel clinical grade adjuvants protamine-RNA complexes (pRNA) and CpG-P...
February 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28183797/ca-2-binding-protein-2-inhibits-ca-2-channel-inactivation-in-mouse-inner-hair-cells
#4
Maria Magdalena Picher, Anna Gehrt, Sandra Meese, Aleksandra Ivanovic, Friederike Predoehl, SangYong Jung, Isabelle Schrauwen, Alberto Giulio Dragonetti, Roberto Colombo, Guy Van Camp, Nicola Strenzke, Tobias Moser
Ca(2+)-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca(2+) channels of type 1.3 (CaV1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2(LacZ/LacZ) ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs)...
February 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28166811/pathogenic-variant-burden-in-the-exac-database-an-empirical-approach-to-evaluating-population-data-for-clinical-variant-interpretation
#5
Yuya Kobayashi, Shan Yang, Keith Nykamp, John Garcia, Stephen E Lincoln, Scott E Topper
BACKGROUND: The frequency of a variant in the general population is a key criterion used in the clinical interpretation of sequence variants. With certain exceptions, such as founder mutations, the rarity of a variant is a prerequisite for pathogenicity. However, defining the threshold at which a variant should be considered "too common" is challenging and therefore diagnostic laboratories have typically set conservative allele frequency thresholds. METHODS: Recent publications of large population sequencing data, such as the Exome Aggregation Consortium (ExAC) database, provide an opportunity to characterize with accuracy and precision the frequency distributions of very rare disease-causing alleles...
February 6, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28157223/novel-variants-in-pax6-gene-caused-congenital-aniridia-in-two-chinese-families
#6
R Zhang, S Linpeng, X Wei, H Li, Y Huang, J Guo, Q Wu, D Liang, L Wu
PurposeTo reveal the underlying genetic defect in two four-generation Chinese families with aniridia and explore the pathologic mechanism.MethodsFull ophthalmic examinations were performed in two families with aniridia. The PAX6 gene was directly sequenced in patients of two families, and the detected variants were screened in unaffected family members and two hundred unrelated healthy controls. Real-time quantitative PCR was used to explore pathologic mechanisms of the two variants.ResultsAniridia, cataract, and oscillatory nystagmus were observed in patients of the two families...
February 3, 2017: Eye
https://www.readbyqxmd.com/read/28145797/characterisation-of-new-generation-aminoglycoside-promoting-premature-termination-codon-readthrough-in-cancer-cells
#7
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/28128343/rna-sequencing-of-synaptic-and-cytoplasmic-upf1-bound-transcripts-supports-contribution-of-nonsense-mediated-decay-to-epileptogenesis
#8
Claire M Mooney, Eva M Jimenez-Mateos, Tobias Engel, Catherine Mooney, Mairead Diviney, Morten T Venø, Jørgen Kjems, Michael A Farrell, Donncha F O'Brien, Norman Delanty, David C Henshall
The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28127254/genetic-separation-of-southern-and-northern-soybean-breeding-programs-in-north-america-and-their-associated-allelic-variation-at-four-maturity-loci
#9
Goettel Wolfgang, Yong-Qiang Charles An
North American soybean breeders have successfully developed a large number of elite cultivars with diverse maturity groups (MG) from a small number of ancestral landraces. To understand molecular and genetic basis underlying the large variation in their maturity and flowering times, we integrated pedigree and maturity data of 166 cultivars representing North American soybean breeding. Network analysis and visualization of their pedigree relationships revealed a clear separation of southern and northern soybean breeding programs, suggesting that little genetic exchange occurred between northern (MG 0-IV) and southern cultivars (MG V-VIII)...
2017: Molecular Breeding: New Strategies in Plant Improvement
https://www.readbyqxmd.com/read/28124995/virus-escape-and-manipulation-of-cellular-nonsense-mediated-mrna-decay
#10
REVIEW
Giuseppe Balistreri, Claudia Bognanni, Oliver Mühlemann
Nonsense-mediated mRNA decay (NMD), a cellular RNA turnover pathway targeting RNAs with features resulting in aberrant translation termination, has recently been found to restrict the replication of positive-stranded RNA ((+)RNA) viruses. As for every other antiviral immune system, there is also evidence of viruses interfering with and modulating NMD to their own advantage. This review will discuss our current understanding of why and how NMD targets viral RNAs, and elaborate counter-defense strategies viruses utilize to escape NMD...
January 23, 2017: Viruses
https://www.readbyqxmd.com/read/28115162/nonstop-mrna-decay-machinery-is-involved-in-the-clearance-of-mrna-5-fragments-produced-by-rnai-and-nmd-in-drosophila-melanogaster-cells
#11
Yoshifumi Hashimoto, Masaki Takahashi, Eri Sakota, Yoshikazu Nakamura
When translating mRNAs are cleaved in protein-coding regions, 5' fragments of mRNAs are detached from stop codons (i.e., nonstop mRNAs) and protected from 3'-5' exonucleases by ribosomes stalled at the 3' termini. It has been shown in yeast that the nonstop mRNA decay (NSD) machinery triggers nonstop mRNA degradation by removing stalled ribosomes in the artificial reporter mRNAs. However, it is not known well whether NSD is involved in the degradation of endogenous nonstop mRNAs in higher eukaryotes. In this work, we addressed the question of whether 5'-nonstop-mRNA fragments generated by siRNA cleavage or nonsense-mediated-mRNA decay (NMD) are degraded by the NSD pathway in Drosophila melanogaster cells by knocking down three NSD components, Pelota (a yeast Dom34 homolog), Hbs1 and ABCE1 (a ribosome-recycling factor)...
January 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28115040/nonsense-mediated-mrna-decay-at-the-crossroads-of-many-cellular-pathways
#12
Fabrice Lejeune
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism ensuring the fast decay of mRNAs harboring a premature termination codon (PTC). As a quality control mechanism, NMD distinguishes PTCs from normal termination codons in order to degrade PTC-carrying mRNAs only. For this, NMD is connected to various other cell processes which regulate or activate it under specific cell conditions or in response to mutations, mis-regulations, stresses, or particular cell programs. These cell processes and their connections with NMD are the focus of this review, which aims both to illustrate the complexity of the NMD mechanism and its regulation and to highlight the cellular consequences of NMD inhibition...
January 24, 2017: BMB Reports
https://www.readbyqxmd.com/read/28095098/reduced-penetrance-in-a-large-caucasian-pedigree-with-stickler-syndrome
#13
Stuart W Tompson, Charles Johnson, Diana Abbott, Benjamin Bakall, Vincent Soler, Tammy L Yanovitch, Kristina N Whisenhunt, Thomas Klemm, Steve Rozen, Edwin M Stone, Max Johnson, Terri L Young
BACKGROUND: In a four-generation Caucasian family variably diagnosed with autosomal dominant (AD) Stickler or Wagner disease, commercial gene screening failed to identify a mutation in COL2A1 or VCAN. We utilized linkage mapping and exome sequencing to identify the causal variant. MATERIALS AND METHODS: Genomic DNA samples collected from 40 family members were analyzed. A whole-genome linkage scan was performed using Illumina HumanLinkage-24 BeadChip followed by two-point and multipoint linkage analyses using FASTLINK and MERLIN...
January 2017: Ophthalmic Genetics
https://www.readbyqxmd.com/read/28077491/sphingosine-1-phosphate-lyase-deficiency-causes-charcot-marie-tooth-neuropathy
#14
Derek Atkinson, Jelena Nikodinovic Glumac, Bob Asselbergh, Biljana Ermanoska, David Blocquel, Regula Steiner, Alejandro Estrada-Cuzcano, Kristien Peeters, Tinne Ooms, Els De Vriendt, Xiang-Lei Yang, Thorsten Hornemann, Vedrana Milic Rasic, Albena Jordanova
OBJECTIVE: To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course. METHODS: Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed...
January 11, 2017: Neurology
https://www.readbyqxmd.com/read/28073787/col6a5-variants-in-familial-neuropathic-chronic-itch
#15
Filippo Martinelli-Boneschi, Marina Colombi, Marco Castori, Grazia Devigili, Roberto Eleopra, Rayaz A Malik, Marco Ritelli, Nicoletta Zoppi, Chiara Dordoni, Melissa Sorosina, Paola Grammatico, Hassan Fadavi, Monique M Gerrits, Rowida Almomani, Catharina G Faber, Ingemar S J Merkies, Daniela Toniolo, Massimiliano Cocca, Claudio Doglioni, Stephen G Waxman, Sulayman D Dib-Hajj, Michela M Taiana, Jenny Sassone, Raffaella Lombardi, Daniele Cazzato, Andrea Zauli, Silvia Santoro, Margherita Marchi, Giuseppe Lauria
Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution...
January 9, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28062855/expression-of-the-erf1-translation-termination-factor-is-controlled-by-an-autoregulatory-circuit-involving-readthrough-and-nonsense-mediated-decay-in-plants
#16
Tünde Nyikó, Andor Auber, Levente Szabadkai, Anna Benkovics, Mariann Auth, Zsuzsanna Mérai, Zoltán Kerényi, Andrea Dinnyés, Ferenc Nagy, Dániel Silhavy
When a ribosome reaches a stop codon, the eukaryotic Release Factor 1 (eRF1) binds to the A site of the ribosome and terminates translation. In yeasts and plants, both over- and underexpression of eRF1 lead to altered phenotype indicating that eRF1 expression should be strictly controlled. However, regulation of eRF1 level is still poorly understood. Here we show that expression of plant eRF1 is controlled by a complex negative autoregulatory circuit, which is based on the unique features of the 3'untranslated region (3'UTR) of the eRF1-1 transcript...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28054750/somatic-med12-nonsense-mutation-escapes-mrna-decay-and-reveals-a-motif-required-for-nuclear-entry
#17
Tuomas Heikkinen, Kati Kämpjärvi, Salla Keskitalo, Pernilla von Nandelstadh, Xiaonan Liu, Ville Rantanen, Esa Pitkänen, Matias Kinnunen, Heikki Kuusanmäki, Mika Kontro, Mikko Turunen, Netta Mäkinen, Jussi Taipale, Caroline Heckman, Kaisa Lehti, Satu Mustjoki, Markku Varjosalo, Pia Vahteristo
MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5' end nonsense mutation (c.97G>T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS)...
March 2017: Human Mutation
https://www.readbyqxmd.com/read/28049534/case-report-maternal-mosaicism-resulting-in-inheritance-of-a-novel-gata6-mutation-causing-pancreatic-agenesis-and-neonatal-diabetes-mellitus
#18
Daphne Yau, Elisa De Franco, Sarah E Flanagan, Sian Ellard, Miriam Blumenkrantz, John J Mitchell
BACKGROUND: Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism. CASE PRESENTATION: The proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents...
January 3, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28027311/somatic-mutation-patterns-in-hemizygous-genomic-regions-unveil-purifying-selection-during-tumor-evolution
#19
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/28017590/fluorescence-amplification-method-for-forward-genetic-discovery-of-factors-in-human-mrna-degradation
#20
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
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