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Nonsense mediated mrna decay

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https://www.readbyqxmd.com/read/28821679/upf1-governs-synaptic-plasticity-through-association-with-a-stau2-rna-granule
#1
Tyson E Graber, Erika Freemantle, Mina Anadolu, Sarah Hébert-Seropian, Robyn MacAdam, Unkyung Shin, Huy-Dung Hoang, Tommy Alain, Jean-Claude Lacaille, Wayne S Sossin
Neuronal mRNAs can be packaged in reversibly stalled polysome granules prior to their transport to distant synaptic locales. Stimulation of synaptic metabotropic glutamate receptors (mGluRs) reactivates translation of these particular mRNAs to produce plasticity-related protein; a phenomenon exhibited during mGluR-mediated long-term depression (mGluR-LTD). This form of plasticity is deregulated in Fragile X Syndrome, a monogenic form of autism in humans, and understanding the stalling and reactivation mechanism could reveal new approaches to therapies...
August 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28813618/whole-exome-sequencing-identifies-novel-variants-for-tooth-agenesis
#2
N Dinckan, R Du, L E Petty, Z Coban-Akdemir, S N Jhangiani, I Paine, E H Baugh, A P Erdem, H Kayserili, H Doddapaneni, J Hu, D M Muzny, E Boerwinkle, R A Gibbs, J R Lupski, Z O Uyguner, J E Below, A Letra
Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis...
August 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28766288/in-vitro-modulation-of-endogenous-alternative-splicing-using-splice-switching-antisense-oligonucleotides
#3
Jeong Eun Park, Luca Cartegni
Regulation of alternative splicing can be harnessed by antisense-based compounds to control gene expression. Antisense-mediated splicing interference has become a valuable molecular tool to modulate endogenous alternative splicing patterns, to correct cryptic or aberrant splicing, to reduce gene expression by triggering nonsense-mediated mRNA decay, and to activate intronic polyadenylation, both in vitro and in vivo. Here, we describe methods to induce and analyze the modulation of RNA processing, using modified splice-switching antisense oligonucleotides, such as phosphorodiamidate morpholino (PMO)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28763028/rous-sarcoma-virus-rna-stability-element-inhibits-deadenylation-of-mrnas-with-long-3-utrs
#4
Vidya Balagopal, Karen L Beemon
All retroviruses use their full-length primary transcript as the major mRNA for Group-specific antigen (Gag) capsid proteins. This results in a long 3' untranslated region (UTR) downstream of the termination codon. In the case of Rous sarcoma virus (RSV), there is a 7 kb 3'UTR downstream of the gag terminator, containing the pol, env, and src genes. mRNAs containing long 3'UTRs, like those with premature termination codons, are frequently recognized by the cellular nonsense-mediated mRNA decay (NMD) machinery and targeted for degradation...
August 1, 2017: Viruses
https://www.readbyqxmd.com/read/28754723/a-functional-link-between-bir1-and-the-saccharomyces-cerevisiae-ctf19-kinetochore-complex-revealed-through-quantitative-fitness-analysis
#5
Vasso Makrantoni, Adam Ciesiolka, Conor Lawless, Josefin Fernius, Adele Marston, David Lydall, Michael J R Stark
The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here we report a genome-wide genetic interaction screen in Saccharomyces cerevisiae using the bir1-17 mutant, identifying through quantitative fitness analysis deletion mutations that act as enhancers and suppressors. Gene knockouts affecting the Ctf19 kinetochore complex were identified as the strongest enhancers of bir1-17, while mutations affecting the large ribosomal subunit or the mRNA nonsense-mediated decay (NMD) pathway caused strong phenotypic suppression...
July 28, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28743738/ptc-readthrough-in-human-cells-occurs-in-novel-cytoplasmic-foci-and-requires-upf-proteins
#6
Jieshuang Jia, Elisabeth Werkmeister, Sara Gonzalez-Hilarion, Catherine Leroy, Dieter C Gruenert, Frank Lafont, David Tulasne, Fabrice Lejeune
Nonsense-mutation-containing messenger ribonucleoprotein particles (mRNPs) transit through cytoplasmic foci called P-bodies before undergoing nonsense-mediated mRNA decay (NMD), a cytoplasmic mRNA surveillance mechanism. This study shows that the cytoskeleton modulates transport of nonsense-mutation-containing mRNPs to and from P-bodies. Impairing the integrity of cytoskeleton causes inhibition of NMD. The cytoskeleton thus plays a crucial role in NMD. Interestingly, disruption of actin filaments results in both inhibition of NMD and activation of readthrough, while disruption of microtubules causes only NMD inhibition...
July 25, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28743675/role-of-nmd-and-nas-in-the-mrna-pattern-of-two-new-%C3%AE-thalassemia-mutants
#7
Giovanna Cardiero, Clelia Scarano, Gennaro Musollino, Francesca Di Noce, Romeo Prezioso, Sabrina Dembech, Gaetana La Porta, Maria Grazia Bisconte, Rosario Colella, Giuseppina Lacerra
The α-thalassemia is a common disease due in prevalence to deletional mutants. We have identified two new α-thalassemia pointform mutants: α1 cod22 GGC > GGT Gly > Gly creating a 5' splicing sequence and: α1 cod23 GAG >TAG Glu > stop. We perform a qualitative and semi-quantitative analysis of the mRNA molecules, from blood of the carriers, to define the molecular mechanisms giving rise to thalassemia phenotype. In vitro analysis using minigenes and cycloheximide was performed to evaluate if the mutants are substrate of nonsense-mediated mRNA decay...
July 22, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28743674/the-role-of-alternative-splicing-coupled-to-nonsense-mediated-mrna-decay-in-human-disease
#8
Paulo J da Costa, Juliane Menezes, Luísa Romão
Alternative pre-mRNA splicing (AS) affects gene expression as it generates proteome diversity. Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and selectively degrades mRNAs carrying premature translation-termination codons (PTCs), preventing the production of truncated proteins that could result in disease. Several studies have also implicated NMD in the regulation of steady-state levels of physiological mRNAs. In addition, it is known that several regulated AS events do not lead to generation of protein products, as they lead to transcripts that carry PTCs and thus, they are committed to NMD...
July 22, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28687732/the-cannabinoid-receptor-interacting-proteins-1-of-zebrafish-are-not-required-for-morphological-development-viability-or-fertility
#9
Laura Fin, Giorgia Bergamin, Roberto A Steiner, Simon M Hughes
The Cannabinoid Receptor Interacting Protein 1 (Cnrip1) was discovered as an interactor with the intracellular region of Cannabinoid Receptor 1 (CB1R, also known as Cnr1 or CB1). Functional assays in mouse show cannabinoid sensitivity changes and Cnrip1 has recently been suggested to control eye development in Xenopus laevis. Two Cnrip1 genes are described in zebrafish, cnrip1a and cnrip1b. In situ mRNA hybridisation revealed accumulation of mRNA encoding each gene primarily in brain and spinal cord, but also elsewhere...
July 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28669802/the-rna-surveillance-factor-upf1-represses-myogenesis-via-its-e3%C3%A2-ubiquitin-ligase-activity
#10
Qing Feng, Sujatha Jagannathan, Robert K Bradley
UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific, normally occurring mRNAs to regulate diverse cellular processes. Here we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically increasing UPF1 levels slows myogenesis...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28663146/human-nonsense-mediated-rna-decay-regulates-emt-by-targeting-the-tgf-%C3%A3-signaling-pathway-in-lung-adenocarcinoma
#11
Lu Cao, Lisha Qi, Lin Zhang, Wangzhao Song, Yue Yu, Cong Xu, Lingmei Li, Yuhong Guo, Lingyi Yang, Changxu Liu, Qiujuan Huang, Yalei Wang, Baocun Sun, Bin Meng, Bin Zhang, Wenfeng Cao
Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that selectively degrades aberrant RNA transcripts. In this study, we proved that NMD regulates the epithelial-mesenchymal transition (EMT) of lung adenocarcinoma (ADC). Moreover, we found that NMD core factor UP-frameshift 1 tends to be expressed at lower levels in human ADC tissues than in normal lung tissues, thereby raising the possibility that NMD may be downregulated to permit ADC oncogenesis. Our experiments in human ADC cell lines showed that downregulating NMD can promote EMT...
June 27, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28663100/a-new-aav10-u7-mediated-gene-therapy-prolongs-survival-and-restores-function-in-an-als-mouse-model
#12
Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD)...
June 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28655137/alzheimer-s-disease-genetics-and-abca7-splicing
#13
Jared B Vasquez, James F Simpson, Ryan Harpole, Steven Estus
Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28634199/characterising-cis-regulatory-variation-in-the-transcriptome-of-histologically-normal-and-tumour-derived-pancreatic-tissues
#14
Mingfeng Zhang, Soren Lykke-Andersen, Bin Zhu, Wenming Xiao, Jason W Hoskins, Xijun Zhang, Lauren M Rost, Irene Collins, Martijn van de Bunt, Jinping Jia, Hemang Parikh, Tongwu Zhang, Lei Song, Ashley Jermusyk, Charles C Chung, Bin Zhu, Weiyin Zhou, Gail L Matters, Robert C Kurtz, Meredith Yeager, Torben Heick Jensen, Kevin M Brown, Halit Ongen, William R Bamlet, Bradley A Murray, Mark I McCarthy, Stephen J Chanock, Nilanjan Chatterjee, Brian M Wolpin, Jill P Smith, Sara H Olson, Gloria M Petersen, Jianxin Shi, Laufey Amundadottir
OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0...
June 20, 2017: Gut
https://www.readbyqxmd.com/read/28634159/a-role-for-the-nonsense-mediated-mrna-decay-pathway-in-maintaining-genome-stability-in-caenorhabditis-elegans
#15
Víctor González-Huici, Bin Wang, Anton Gartner
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand-breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hypersensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) kinase involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signalling pathways...
June 20, 2017: Genetics
https://www.readbyqxmd.com/read/28619046/identification-of-a-novel-ctcf-mutation-responsible-for-syndromic-intellectual-disability-a-case-report
#16
Fatma Bastaki, Pratibha Nair, Madiha Mohamed, Ethar Mustafa Malik, Mustafa Helmi, Mahmoud Taleb Al-Ali, Abdul Rezzak Hamzeh
BACKGROUND: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor...
June 15, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28608987/smarca4-inactivating-mutations-cause-concomitant-coffin-siris-syndrome-microphthalmia-and-small-cell-carcinoma-of-the-ovary-hypercalcemic-type
#17
Edoardo Errichiello, Noor Mustafa, Annalisa Vetro, Lucia Dora Notarangelo, Hugo de Jonge, Berardo Rinaldi, Debora Vergani, Sabrina Rita Giglio, Patrizia Morbini, Orsetta Zuffardi
SMARCA4 chromatin remodeling factor is mutated in 11% of Coffin-Siris syndrome (CSS) patients and in almost all small cell carcinoma of the ovary hypercalcemic type (SCCOHT) tumors. Missense mutations with gain-of-function or dominant-negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole exome sequencing to study a 15-year-old patient with mild CSS who concomitantly developed SCCOHT at age 13 years...
June 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28588666/molecular-analysis-of-the-novel-ids-allele-in-a-thai-family-with-mucopolysaccharidosis-type-ii-the-c-928c-t-p-gln310-transcript-is-sensitive-to-nonsense-mediated-mrna-decay
#18
Lukana Ngiwsara, Kitiwan Rojnueangnit, Duangrurdee Wattanasirichaigoon, Thipwimol Tim-Aroon, Phannee Sawangareetrakul, Voraratt Champattanachai, James R Ketudat-Cairns, Jisnuson Svasti
Hunter syndrome (or mucopolysaccharidosis type II, MPS II) is an X-linked recessive disorder induced by a deficiency of the iduronate 2-sulfatase (IDS) enzyme, resulting in the accumulation of glycosaminoglycan substrates, heparan sulfate and dermatan sulfate, in the lysosomes. The progressive accumulation of undegraded metabolites induces cell and tissue dysfunction, leading to multi-systemic pathology. The heterogeneity of clinical phenotypes, ranging from mild to severe forms, results from different mutations in the IDS gene...
June 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28586478/autoregulation-of-rbm10-and-cross-regulation-of-rbm10-rbm5-via-alternative-splicing-coupled-nonsense-mediated-decay
#19
Yue Sun, Yufang Bao, Wenjian Han, Fan Song, Xianfeng Shen, Jiawei Zhao, Ji Zuo, David Saffen, Wei Chen, Zefeng Wang, Xintian You, Yongbo Wang
Mutations in the spliceosomal RNA binding protein RBM10 cause TARP syndrome and are frequently observed in lung adenocarcinoma (LUAD). We have previously shown that RBM10 enhances exon skipping of its target genes, including its paralog RBM5. Here, we report that RBM10 negatively regulates its own mRNA and protein expression and that of RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD). Through computational analysis and experimental validation, we identified RBM10-promoted skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 as the underlying AS-NMD events...
June 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28570605/frameshift-indels-introduced-by-genome-editing-can-lead-to-in-frame-exon-skipping
#20
Simon Lalonde, Oliver A Stone, Samuel Lessard, Adam Lavertu, Jessica Desjardins, Mélissa Beaudoin, Manuel Rivas, Didier Y R Stainier, Guillaume Lettre
The introduction of frameshift indels by genome editing has emerged as a powerful technique to study the functions of uncharacterized genes in cell lines and model organisms. Such mutations should lead to mRNA degradation owing to nonsense-mediated mRNA decay or the production of severely truncated proteins. Here, we show that frameshift indels engineered by genome editing can also lead to skipping of "multiple of three nucleotides" exons. Such splicing events result in in-frame mRNA that may encode fully or partially functional proteins...
2017: PloS One
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