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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/28821630/il-17a-deficiency-mitigates-bleomycin-induced-complement-activation-during-lung-fibrosis
#2
Ellyse Cipolla, Amanda J Fisher, Hongmei Gu, Elizabeth A Mickler, Manisha Agarwal, Carol A Wilke, Kevin K Kim, Bethany B Moore, Ragini Vittal
Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3, and GPCR kinase isoform 5), cytokines (IL8, -6, and -1B), and cytokine ligands (CXCL1, -2, -3, -5, -6, and -16)...
August 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28817234/osmium-mediated-4su-to-c-transformation-as-key-to-study-rna-dynamics-by-sequencing-tuc-seq
#3
Christian Riml, Thomas Amort, Dietmar Rieder, Catherina Gasser, Alexandra Lusser, Ronald Micura
To understand the functional roles of RNA in the cell, it is essential to elucidate the dynamics of their production, processing and decay. A recent method for assessing mRNA dynamics is metabolic labeling with 4-thiouridine (4sU), followed by thio-selective attachment of affinity tags. Detection of labeled transcripts by affinity purification and hybridization to microarrays or by deep sequencing then reveals RNA expression levels. Here, we present a novel sequencing method that eliminates affinity purification and allows for direct assessment of 4sU labeled RNA...
August 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28813618/whole-exome-sequencing-identifies-novel-variants-for-tooth-agenesis
#4
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/28809393/ythdc2-is-an-n-6-methyladenosine-binding-protein-that-regulates-mammalian-spermatogenesis
#5
Phillip J Hsu, Yunfei Zhu, Honghui Ma, Yueshuai Guo, Xiaodan Shi, Yuanyuan Liu, Meijie Qi, Zhike Lu, Hailing Shi, Jianying Wang, Yiwei Cheng, Guanzheng Luo, Qing Dai, Mingxi Liu, Xuejiang Guo, Jiahao Sha, Bin Shen, Chuan He
N(6)-methyladenosine (m(6)A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m(6)A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m(6)A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown...
August 15, 2017: Cell Research
https://www.readbyqxmd.com/read/28802259/cis-regulatory-elements-explain-most-of-the-mrna-stability-variation-across-genes-in-yeast
#6
Jun Cheng, Kerstin C Maier, Ziga Avsec, Petra Rus, Julien Gagneur
The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3'UTR motif, ATATTC, which we functionally validated...
August 11, 2017: RNA
https://www.readbyqxmd.com/read/28795788/new-molecular-insights-into-an-archaeal-rnase-j-reveal-a-conserved-processive-exoribonucleolysis-mechanism-of-the-rnase-j-family
#7
Xin Zheng, Na Feng, Defeng Li, Xiuzhu Dong, Jie Li
RNase J, a prokaryotic 5'-3' exo/endoribonuclease, contributes to mRNA decay, rRNA maturation, and post-transcriptional regulation. Yet the processive-exoribonucleolysis mechanism remains obscure. Here, we solved the first RNA-free and RNA-bound structures of an archaeal RNase J, and through intensive biochemical studies provided detailed mechanistic insights into the catalysis and processivity. Distinct dimerization/tetramerization patterns were observed for archaeal and bacterial RNase Js, and unique archaeal Loops I and II were found involved in RNA interaction...
August 10, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28795162/global-survey-of-mrna-levels-and-decay-rates-of-chlamydia-trachomatis-trachoma-and-lymphogranuloma-venereum-biovars
#8
Rita Ferreira, Vítor Borges, Maria José Borrego, João Paulo Gomes
Interpreting the intricate bacterial transcriptomics implies understanding the dynamic relationship established between de novo transcription and the degradation of transcripts. Here, we performed a comparative overview of gene expression levels and mRNA decay rates for different-biovar (trachoma and lymphogranuloma venereum) strains of the obligate intracellular bacterium Chlamydia trachomatis. By using RNA-sequencing to measure gene expression levels at mid developmental stage and mRNA decay rates upon rifampicin-based transcription blockage, we observed that: i) 60-70% of the top-50 expressed genes encode proteins with unknown function and proteins involved in "Translation, ribosomal structure and biogenesis" for all strains; ii) the expression ranking by genes' functional categories was in general concordant among different-biovar strains; iii) the median of the half-life time (t1/2) values of transcripts were 15-17 min, indicating that the degree of transcripts' stability seems to correlate with the bacterial intracellular life-style, as these values are considerably higher than the ones observed in other studies for facultative intracellular and free-living bacteria; iv) transcript decay rates were highly heterogeneous within each C...
July 2017: Heliyon
https://www.readbyqxmd.com/read/28792938/m-6-a-mrna-methylation-controls-t-cell-homeostasis-by-targeting-the-il-7-stat5-socs-pathways
#9
Hua-Bing Li, Jiyu Tong, Shu Zhu, Pedro J Batista, Erin E Duffy, Jun Zhao, Will Bailis, Guangchao Cao, Lina Kroehling, Yuanyuan Chen, Geng Wang, James P Broughton, Y Grace Chen, Yuval Kluger, Matthew D Simon, Howard Y Chang, Zhinan Yin, Richard A Flavell
N(6)-methyladenosine (m(6)A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m(6)A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m(6)A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation...
August 9, 2017: Nature
https://www.readbyqxmd.com/read/28782243/the-la-and-related-rna-binding-proteins-larps-structures-functions-and-evolving-perspectives
#10
REVIEW
Richard J Maraia, Sandy Mattijssen, Isabel Cruz-Gallardo, Maria R Conte
La was first identified as a polypeptide component of ribonucleic protein complexes targeted by antibodies in autoimmune patients and is now known to be a eukaryote cell-ubiquitous protein. Structure and function studies have shown that La binds to a common terminal motif, UUU-3'-OH, of nascent RNA polymerase III (RNAP III) transcripts and protects them from exonucleolytic decay. For precursor-tRNAs, the most diverse and abundant of these transcripts, La also functions as an RNA chaperone that helps to prevent their misfolding...
August 7, 2017: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/28771467/comprehensive-analysis-of-nucleocytoplasmic-dynamics-of-mrna-in-drosophila-cells
#11
Tao Chen, Bas van Steensel
Eukaryotic mRNAs undergo a cycle of transcription, nuclear export, and degradation. A major challenge is to obtain a global, quantitative view of these processes. Here we measured the genome-wide nucleocytoplasmic dynamics of mRNA in Drosophila cells by metabolic labeling in combination with cellular fractionation. By mathematical modeling of these data we determined rates of transcription, export and cytoplasmic decay for 5420 genes. We characterized these kinetic rates and investigated links with mRNA features, RNA-binding proteins (RBPs) and chromatin states...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28768202/dual-rna-processing-roles-of-pat1b-via-cytoplasmic-lsm1-7-and-nuclear-lsm2-8-complexes
#12
Caroline Vindry, Aline Marnef, Helen Broomhead, Laure Twyffels, Sevim Ozgur, Georg Stoecklin, Miriam Llorian, Christopher W Smith, Juan Mata, Dominique Weil, Nancy Standart
Pat1 RNA-binding proteins, enriched in processing bodies (P bodies), are key players in cytoplasmic 5' to 3' mRNA decay, activating decapping of mRNA in complex with the Lsm1-7 heptamer. Using co-immunoprecipitation and immunofluorescence approaches coupled with RNAi, we provide evidence for a nuclear complex of Pat1b with the Lsm2-8 heptamer, which binds to the spliceosomal U6 small nuclear RNA (snRNA). Furthermore, we establish the set of interactions connecting Pat1b/Lsm2-8/U6 snRNA/SART3 and additional U4/U6...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28766288/in-vitro-modulation-of-endogenous-alternative-splicing-using-splice-switching-antisense-oligonucleotides
#13
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
#14
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
#15
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/28754144/a-novel-mechanism-for-variable-phenotypic-expressivity-in-mendelian-diseases-uncovered-by-an-au-rich-element-are-creating-mutation
#16
Nisha Patel, Arif O Khan, Maher Al-Saif, Walid N Moghrabi, Balsam M AlMaarik, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Tarfa Alshidi, Eman Alobeid, Rana A Alomar, Saad Al-Harbi, Mohamed Abouelhoda, Khalid S A Khabar, Fowzan S Alkuraya
BACKGROUND: Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic. RESULTS: We report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3' UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement...
July 28, 2017: Genome Biology
https://www.readbyqxmd.com/read/28743738/ptc-readthrough-in-human-cells-occurs-in-novel-cytoplasmic-foci-and-requires-upf-proteins
#17
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
#18
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
#19
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/28740488/regulatory-3-untranslated-regions-of-bacterial-mrnas
#20
REVIEW
Gai-Xian Ren, Xiao-Peng Guo, Yi-Cheng Sun
The untranslated regions (UTRs) of mRNA contain important features that are relevant to the post-transcriptional and translational regulation of gene expression. Most studies of bacterial UTRs have focused on the 5'regions; however, 3'UTRs have recently emerged as a new class of post-transcriptional regulatory elements. 3'UTRs were found to regulate the decay and translation initiation in their own mRNAs. In addition, 3'UTRs constitute a rich reservoir of small regulatory RNAs, regulating target gene expression...
2017: Frontiers in Microbiology
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