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exon junction complexes

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https://www.readbyqxmd.com/read/27879206/exon-junction-complex-proteins-bind-nascent-transcripts-independently-of-pre-mrna-splicing-in-drosophila-melanogaster
#1
Subhendu Roy Choudhury, Anand K Singh, Tina McLeod, Marco Blanchette, Boyun Jang, Paul Badenhorst, Aditi Kanhere, Saverio Brogna
Although it is currently understood that the exon junction complex (EJC) is recruited on spliced mRNA by a specific interaction between its central protein, eIF4AIII, and splicing factor CWC22, we found that eIF4AIII and the other EJC core proteins Y14 and MAGO bind the nascent transcripts of not only intron-containing but also intronless genes on Drosophila polytene chromosome. Additionally, Y14 ChIP-seq demonstrates that association with transcribed genes is also splicing-independent in Drosophila S2 cells...
November 23, 2016: ELife
https://www.readbyqxmd.com/read/27874031/harnessing-short-poly-a-binding-protein-interacting-peptides-for-the-suppression-of-nonsense-mediated-mrna-decay
#2
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
https://www.readbyqxmd.com/read/27867087/a-quantitative-immunoassay-for-lung-cancer-biomarker-ciz1b-in-patient-plasma
#3
Dawn Coverley, Gillian Higgins, Daniel West, Oliver T Jackson, Adam Dowle, Aidan Haslam, Eve Ainscough, Rebecca Chalkey, John White
OBJECTIVES: Non-invasive tests for early detection of lung cancer are an important unmet clinical need. CIZ1b plasma biomarker can discriminate stage 1 lung cancer from within high-risk groups with clinically useful accuracy, with ROC AUCs in excess of 0.9 for two independent retrospective cohorts, and could therefore meet this need. Our aim was to characterise the native state of the biomarker and develop a quantitative immunoassay. DESIGN AND METHODS: Selective denaturation, preparative electrophoresis and mass spectrometry of human plasma were used to characterise the biomarker and interaction partners...
November 17, 2016: Clinical Biochemistry
https://www.readbyqxmd.com/read/27854212/non-random-distribution-of-dmd-deletion-breakpoints-and-implication-of-double-strand-breaks-repair-and-replication-error-repair-mechanisms
#4
Isabelle Marey, Rabah Ben Yaou, Nathalie Deburgrave, Aurélie Vasson, Juliette Nectoux, France Leturcq, Bruno Eymard, Pascal Laforet, Anthony Behin, Tanya Stojkovic, Michèle Mayer, Vincent Tiffreau, Isabelle Desguerre, François Constant Boyer, Aleksandra Nadaj-Pakleza, Xavier Ferrer, Karim Wahbi, Henri-Marc Becane, Mireille Claustres, Jamel Chelly, Mireille Cossee
BACKGROUND: Dystrophinopathies are mostly caused by copy number variations, especially deletions, in the dystrophin gene (DMD). Despite the large size of the gene, deletions do not occur randomly but mainly in two hot spots, the main one involving exons 45 to 55. The underlying mechanisms are complex and implicate two main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated replication-dependent recombination (MMRDR). OBJECTIVE: Our goals were to assess the distribution of intronic breakpoints (BPs) in the genomic sequence of the main hot spot of deletions within DMD gene and to search for specific sequences at or near to BPs that might promote BP occurrence or be associated with DNA break repair...
May 27, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27798850/identification-and-molecular-characterization-of-cellular-factors-required-for-glucocorticoid-receptor-mediated-mrna-decay
#5
Ok Hyun Park, Joori Park, Mira Yu, Hyoung-Tae An, Jesang Ko, Yoon Ki Kim
Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complex-independent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1)...
September 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27780844/mouse-models-of-casc3-reveal-developmental-functions-distinct-from-other-components-of-the-exon-junction-complex
#6
Hanqian Mao, Hannah E Brown, Debra L Silver
The exon junction complex (EJC) is a multi-protein complex integral to RNA metabolism. Biochemistry and genetic studies have concluded that the EJC is composed of 4 core proteins, MAGOH, EIF4A3, RBM8A, and CASC3. Yet recent studies in Drosophila indicate divergent functions for Barentsz, the mammalian Casc3 ortholog, raising the question as to whether CASC3 is a constitutive component of the EJC. This issue remains poorly understood, particularly in an in vivo mammalian context. We previously found that haploinsufficiency for Magoh, Eif4a3, or Rbm8a disrupts neuronal viability and neural progenitor proliferation, resulting in severe microcephaly...
October 25, 2016: RNA
https://www.readbyqxmd.com/read/27684375/alternative-isoform-analysis-of-ttc8-expression-in-the-rat-pineal-gland-using-a-multi-platform-sequencing-approach-reveals-neural-regulation
#7
Stephen W Hartley, James C Mullikin, David C Klein, Morgan Park, Steven L Coon
Alternative isoform regulation (AIR) vastly increases transcriptome diversity and plays an important role in numerous biological processes and pathologies. However, the detection and analysis of isoform-level differential regulation is difficult, particularly in the face of complex and incompletely-annotated transcriptomes. Here we have used Illumina short-read/high-throughput RNA-Seq to identify 55 genes that exhibit neurally-regulated AIR in the pineal gland, and then used two other complementary experimental platforms to further study and characterize the Ttc8 gene, which is involved in Bardet-Biedl syndrome and non-syndromic retinitis pigmentosa...
2016: PloS One
https://www.readbyqxmd.com/read/27681125/the-splicing-history-of-an-mrna-affects-its-level-of-translation-and-sensitivity-to-cleavage-by-the-virion-host-shutoff-endonuclease-during-herpes-simplex-virus-infections
#8
Jouliana Sadek, G Sullivan Read
: During lytic herpes simplex virus (HSV) infections, the virion host shutoff (Vhs) (UL41) endoribonuclease degrades many cellular and viral mRNAs. In uninfected cells, spliced mRNAs emerge into the cytoplasm bound by exon junction complexes (EJCs) and are translated several times more efficiently than unspliced mRNAs that have the same sequence but lack EJCs. Notably, most cellular mRNAs are spliced, whereas most HSV mRNAs are not. To examine the effect of splicing on gene expression during HSV infection, cells were transfected with plasmids harboring an unspliced renilla luciferase (RLuc) reporter mRNA or RLuc constructs with introns near the 5' or 3' end of the gene...
December 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27667727/exon-junction-complexes-supervising-the-gene-expression-assembly-line
#9
Volker Boehm, Niels H Gehring
The exon junction complex (EJC) is an RNA-binding protein complex that is assembled and deposited onto mRNAs during splicing. The EJC comprises four core components that bind to not only canonical sites upstream of exon-exon junctions, but also to noncanonical sites at other positions in exons. EJC-associated proteins are recruited by the EJC at different steps of gene expression to execute the multiple functions of the EJC. Recently, new insights have been obtained into how EJCs stimulate pre-mRNA splicing, and mRNA export, translation, and degradation...
November 2016: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/27618451/the-rules-and-impact-of-nonsense-mediated-mrna-decay-in-human-cancers
#10
Rik G H Lindeboom, Fran Supek, Ben Lehner
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs...
October 2016: Nature Genetics
https://www.readbyqxmd.com/read/27618312/haploinsufficiency-for-core-exon-junction-complex-components-disrupts-embryonic-neurogenesis-and-causes-p53-mediated-microcephaly
#11
Hanqian Mao, John J McMahon, Yi-Hsuan Tsai, Zefeng Wang, Debra L Silver
The exon junction complex (EJC) is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling...
September 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27557076/a-method-for-identifying-discriminative-isoform-specific-peptides-for-clinical-proteomics-application
#12
Fan Zhang, Jake Y Chen
BACKGROUND: Clinical proteomics application aims at solving a specific clinical problem within the context of a clinical study. It has been growing rapidly in the field of biomarker discovery, especially in the area of cancer diagnostics. Until recently, protein isoform has not been viewed as a new class of early diagnostic biomarkers for clinical proteomics. A protein isoform is one of different forms of the same protein. Different forms of a protein may be produced from single-nucleotide polymorphisms (SNPs), alternative splicing, or post-translational modifications (PTMs)...
2016: BMC Genomics
https://www.readbyqxmd.com/read/27536874/the-exon-junction-complex-regulates-the-splicing-of-cell-polarity-gene-dlg1-to-control-wingless-signaling-in-development
#13
Min Liu, Yajuan Li, Aiguo Liu, Ruifeng Li, Ying Su, Juan Du, Cheng Li, Alan Jian Zhu
Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh...
2016: ELife
https://www.readbyqxmd.com/read/27525442/calpain-6-confers-atherogenicity-to-macrophages-by-dysregulating-pre-mrna-splicing
#14
Takuro Miyazaki, Kazuo Tonami, Shoji Hata, Toshihiro Aiuchi, Koji Ohnishi, Xiao-Feng Lei, Joo-Ri Kim-Kaneyama, Motohiro Takeya, Hiroyuki Itabe, Hiroyuki Sorimachi, Hiroki Kurihara, Akira Miyazaki
Macrophages contribute to the development of atherosclerosis through pinocytotic deposition of native LDL-derived cholesterol in macrophages in the vascular wall. Inhibiting macrophage-mediated lipid deposition may have protective effects in atheroprone vasculature, and identifying mechanisms that potentiate this process may inform potential therapeutic interventions for atherosclerosis. Here, we report that dysregulation of exon junction complex-driven (EJC-driven) mRNA splicing confers hyperpinocytosis to macrophages during atherogenesis...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27490541/the-exon-junction-complex-controls-the-efficient-and-faithful-splicing-of-a-subset-of-transcripts-involved-in-mitotic-cell-cycle-progression
#15
Kazuhiro Fukumura, Shunichi Wakabayashi, Naoyuki Kataoka, Hiroshi Sakamoto, Yutaka Suzuki, Kenta Nakai, Akila Mayeda, Kunio Inoue
The exon junction complex (EJC) that is deposited onto spliced mRNAs upstream of exon-exon junctions plays important roles in multiple post-splicing gene expression events, such as mRNA export, surveillance, localization, and translation. However, a direct role for the human EJC in pre-mRNA splicing has not been fully understood. Using HeLa cells, we depleted one of the EJC core components, Y14, and the resulting transcriptome was analyzed by deep sequencing (RNA-Seq) and confirmed by RT-PCR. We found that Y14 is required for efficient and faithful splicing of a group of transcripts that is enriched in short intron-containing genes involved in mitotic cell-cycle progression...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27475226/exon-junction-complexes-show-a-distributional-bias-toward-alternatively-spliced-mrnas-and-against-mrnas-coding-for-ribosomal-proteins
#16
Christian Hauer, Jana Sieber, Thomas Schwarzl, Ina Hollerer, Tomaz Curk, Anne-Marie Alleaume, Matthias W Hentze, Andreas E Kulozik
The exon junction complex (EJC) connects spliced mRNAs to posttranscriptional processes including RNA localization, transport, and regulated degradation. Here, we provide a comprehensive analysis of bona fide EJC binding sites across the transcriptome including all four RNA binding EJC components eIF4A3, BTZ, UPF3B, and RNPS1. Integration of these data sets permits definition of high-confidence EJC deposition sites as well as assessment of whether EJC heterogeneity drives alternative nonsense-mediated mRNA decay pathways...
August 9, 2016: Cell Reports
https://www.readbyqxmd.com/read/27365210/the-fission-yeast-mtrec-and-ejc-orthologs-ensure-the-maturation-of-meiotic-transcripts-during-meiosis
#17
Bahjat Fadi Marayati, Victoria Hoskins, Robert W Boger, James F Tucker, Emily S Fishman, Andrew S Bray, Ke Zhang
Meiosis is a highly regulated process by which genetic information is transmitted through sexual reproduction. It encompasses unique mechanisms that do not occur in vegetative cells, producing a distinct, well-regulated meiotic transcriptome. During vegetative growth, many meiotic genes are constitutively transcribed, but most of the resulting mRNAs are rapidly eliminated by the Mmi1-MTREC (Mtl1-Red1 core) complex. While Mmi1-MTREC targets premature meiotic RNAs for degradation by the nuclear 3'-5' exoribonuclease exosome during mitotic growth, its role in meiotic gene expression during meiosis is not known...
September 2016: RNA
https://www.readbyqxmd.com/read/27365209/the-rna-binding-profile-of-acinus-a-peripheral-component-of-the-exon-junction-complex-reveals-its-role-in-splicing-regulation
#18
Julie Rodor, Qun Pan, Benjamin J Blencowe, Eduardo Eyras, Javier F Cáceres
Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs...
September 2016: RNA
https://www.readbyqxmd.com/read/27291164/nuclear-proteomics-reveals-the-role-of-protein-synthesis-and-chromatin-structure-in-root-tip-of-soybean-during-the-initial-stage-of-flooding-stress
#19
Xiaojian Yin, Setsuko Komatsu
To identify the upstream events controlling the regulation of flooding-responsive proteins in soybean, proteomic analysis of nuclear proteins in root tip was performed. By using nuclear fractions, which were highly enriched, a total of 365 nuclear proteins were changed in soybean root tip at initial stage of flooding stress. Four exon-junction complex-related proteins and NOP1/NOP56, which function in upstream of 60S preribosome biogenesis, were decreased in flooded soybean. Furthermore, proteomic analysis of crude protein extract revealed that the protein translation was suppressed by continuous flooding stress...
July 1, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27221324/nonsense-mediated-mrna-decay-factor-upf2-exists-in-both-the-nucleoplasm-and-the-cytoplasm
#20
Takanori Tatsuno, Yuka Nakamura, Shaofu Ma, Naohisa Tomosugi, Yasuhito Ishigaki
Upf2 protein predominantly localizes to the cytoplasmic fraction, and binds to the exon junction complex (EJC) on spliced mRNA. The present study aimed to determine the cellular site where the interaction between Upf2 and EJC occurs. First, the cell lysate was fractionated into the cytoplasm and nucleoplasm, and western blotting to detect levels of Upf2 protein was performed. Upf2 was clearly detected in the cytoplasm and in the nucleoplasm. Secondly, immunostaining was performed, and the majority of Upf2 was detected in the cytoplasmic perinuclear region; a small quantity of Upf2 was detected in the intranuclear region...
July 2016: Molecular Medicine Reports
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