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mRNA decay

Etienne Raimondeau, Joshua C Bufton, Christiane Schaffitzel
Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3'-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs...
April 6, 2018: Biochemical Society Transactions
Hyeshik Chang, Jinah Yeo, Jeong-Gyun Kim, Hyunjoon Kim, Jaechul Lim, Mihye Lee, Hyun Ho Kim, Jiyeon Ohk, Hee-Yeon Jeon, Hyunsook Lee, Hosung Jung, Kyu-Won Kim, V Narry Kim
During the maternal-to-zygotic transition (MZT), maternal RNAs are actively degraded and replaced by newly synthesized zygotic transcripts in a highly coordinated manner. However, it remains largely unknown how maternal mRNA decay is triggered in early vertebrate embryos. Here, through genome-wide profiling of RNA abundance and 3' modification, we show that uridylation is induced at the onset of maternal mRNA clearance. The temporal control of uridylation is conserved in vertebrates. When the homologs of terminal uridylyltransferases TUT4 and TUT7 (TUT4/7) are depleted in zebrafish and Xenopus, maternal mRNA clearance is significantly delayed, leading to developmental defects during gastrulation...
April 5, 2018: Molecular Cell
Daniel J Luciano, Nikita Vasilyev, Jamie Richards, Alexander Serganov, Joel G Belasco
Deprotection of the 5' end appears to be a universal mechanism for triggering the degradation of mRNA in bacteria and eukaryotes. In Escherichia coli, for example, converting the 5' triphosphate of primary transcripts to a monophosphate accelerates cleavage at internal sites by the endonuclease RNase E. Previous studies have shown that the RNA pyrophosphohydrolase RppH catalyzes this transformation in vitro and generates monophosphorylated decay intermediates in vivo. Recently, we reported that purified E. coli RppH unexpectedly reacts faster with diphosphorylated than with triphosphorylated substrates...
April 5, 2018: RNA Biology
David R Paquette, Ryan W Tibble, Tristan S Daifuku, John D Gross
5' mediated cytoplasmic RNA decay is a conserved cellular process in eukaryotes. While the functions of the structured core domains in this pathway are well-studied, the role of abundant intrinsically disordered regions (IDRs) is lacking. Here we reconstitute the Dcp1:Dcp2 complex containing a portion of the disordered C-terminus and show its activity is autoinhibited by linear interaction motifs. Enhancers of decapping (Edc) 1 and 3 cooperate to activate decapping by different mechanisms: Edc3 alleviates autoinhibition by binding IDRs and destabilizing an inactive form of the enzyme, whereas Edc1 stabilizes the transition state for catalysis...
March 29, 2018: Nucleic Acids Research
Melissa Verkaik, Maarten Oranje, Desiree Abdurrachim, Max Goebel, Zeineb Gam, Jeanine J Prompers, Michiel Helmes, Pieter M Ter Wee, Jolanda van der Velden, Diederik W Kuster, Marc G Vervloet, Etto C Eringa
The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs...
April 2018: Physiological Reports
James P B Lloyd, Daniel Lang, Andreas D Zimmer, Barry Causier, Ralf Reski, Brendan Davies
Nonsense-mediated mRNA decay (NMD) is important for RNA quality control and gene regulation in eukaryotes. NMD targets aberrant transcripts for decay and also directly influences the abundance of non-aberrant transcripts. In animals, the SMG1 kinase plays an essential role in NMD by phosphorylating the core NMD factor UPF1. Despite SMG1 being ubiquitous throughout the plant kingdom, little is known about its function, probably because SMG1 is atypically absent from the genome of the model plant, Arabidopsis thaliana...
March 27, 2018: Nucleic Acids Research
Izabela Wawer, Anna Golisz, Aleksandra Sulkowska, Dorota Kawa, Anna Kulik, Joanna Kufel
Defects in RNA processing and degradation pathways often lead to developmental abnormalities, impaired hormonal signaling and altered resistance to abiotic and biotic stress. Here we report that components of the 5'-3' mRNA decay pathway, DCP5, LSM1-7 and XRN4, contribute to a proper response to a key plant hormone abscisc acid (ABA), albeit in a different manner. Plants lacking DCP5 are more sensitive to ABA during germination, whereas lsm1a lsm1b and xrn4-5 mutants are affected at the early stages of vegetative growth...
2018: Frontiers in Plant Science
Lamya El Mortaji, Sylvie Aubert, Eloïse Galtier, Christine Schmitt, Karine Anger, Yulia Redko, Yves Quentin, Hilde De Reuse
Present in every kingdom of life, generally in multiple copies, DEAD-box RNA helicases are specialized enzymes that unwind RNA secondary structures. They play major roles in mRNA decay, ribosome biogenesis, and adaptation to cold temperatures. Most bacteria have multiple DEAD-box helicases that present both specialized and partially redundant functions. By using phylogenomics, we revealed that the Helicobacter genus, including the major gastric pathogen H. pylori , is among the exceptions, as it encodes a sole DEAD-box RNA helicase...
March 27, 2018: MBio
Bérengère de Toeuf, Romuald Soin, Abdelkarim Nazih, Marija Dragojevic, Dukas Jurėnas, Nadège Delacourt, Long Vo Ngoc, Abel Garcia-Pino, Véronique Kruys, Cyril Gueydan
Hypoxia triggers profound modifications of cellular transcriptional programs. Upon reoxygenation, cells return to a normoxic gene expression pattern and mRNA produced during the hypoxic phase are degraded. TIS11 proteins control deadenylation and decay of transcripts containing AU-rich elements (AREs). We observed that the level of dTIS11 is decreased in hypoxic S2 Drosophila cells and returns to normal level upon reoxygenation. Bioinformatic analyses using the ARE-assessing algorithm AREScore show that the hypoxic S2 transcriptome is enriched in ARE-containing transcripts and that this trend is conserved in human myeloid cells...
March 26, 2018: Scientific Reports
Fei Dong, Cen Li, Pu Wang, Xiaoya Deng, Qinli Luo, Xiaokui Tang, Li Xu
Tristetraprolin (TTP) is the most well-known member of RNA-binding zinc-finger protein that play a significant role in accelerating mRNA decay. Increasingly studies have reported that TTP was functioned as a tumor suppressor gene in several types of carcinomas, while its underlying mechanism is not clear yet. In the current study, we found that TTP overexpression decreased cell proliferation and increased cell death in lung adenocarcinoma cells, with the cell cycle arrest at the S phase. Remarkably, instead of inducing cell apoptosis directly, TTP overexpression alters cell autophagy...
March 22, 2018: Experimental Cell Research
Tomasz Herjan, Lingzi Hong, Jodi Bubenik, Katarzyna Bulek, Wen Qian, Caini Liu, Xiao Li, Xing Chen, Hui Yang, Suidong Ouyang, Hao Zhou, Junjie Zhao, Kommireddy Vasu, Eric Cockman, Mark Aronica, Kewal Asosingh, Donny D Licatalosi, Jun Qin, Paul L Fox, Thomas A Hamilton, Donna Driscoll, Xiaoxia Li
Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation...
April 2018: Nature Immunology
Kathryn E Pendleton, Sung Kyun Park, Olga V Hunter, Stefan M Bresson, Nicholas K Conrad
Transcriptome analysis of human cells has revealed that intron retention controls the expression of a large number of genes with diverse cellular functions. Detained introns (DI) constitute a subgroup of transcripts with retained introns that are not exported to the cytoplasm but instead remain in the nucleus. Previous studies reported that the splicing of DIs in the CLK1 transcript are posttranscriptionally induced to produce mature mRNA in the absence of new transcription. Thus, CLK1-DI serves as a precursor or "reservoir" for the CLK1 mRNA...
March 21, 2018: RNA
Andrew C Peifer, Patrick H Maxwell
Retrotransposons are abundant mobile DNA elements in eukaryotic genomes that are more active with age in diverse species. Details of the regulation and consequences of retrotransposon activity during aging remain to be determined. Ty1 retromobility in Saccharomyces cerevisiae is more frequent in mother cells compared to daughter cells, and we found that Ty1 was more mobile in nonquiescent compared to quiescent subpopulations of stationary phase cells. This retromobility asymmetry was absent in mutant strains lacking BRP1 that have reduced expression of the essential Pma1p plasma membrane proton pump, lacking the mRNA decay gene LSM1 , and in cells exposed to a high concentration of calcium...
March 21, 2018: Aging
Bridget P Bannerman, Susanne Kramer, Richard G Dorrell, Mark Carrington
The degree of conservation and evolution of cytoplasmic mRNA metabolism pathways across the eukaryotes remains incompletely resolved. In this study, we describe a comprehensive genome and transcriptome-wide analysis of proteins involved in mRNA maturation, translation, and mRNA decay across representative organisms from the six eukaryotic super-groups. We demonstrate that eukaryotes share common pathways for mRNA metabolism that were almost certainly present in the last eukaryotic common ancestor, and show for the first time a correlation between intron density and a selective absence of some Exon Junction Complex (EJC) components in eukaryotes...
2018: PloS One
Nazmul Haque, Ryota Ouda, Chao Chen, Keiko Ozato, J Robert Hogg
Control of type I interferon production is crucial to combat infection while preventing deleterious inflammatory responses, but the extent of the contribution of post-transcriptional mechanisms to innate immune regulation is unclear. Here, we show that human zinc finger RNA-binding protein (ZFR) represses the interferon response by regulating alternative pre-mRNA splicing. ZFR expression is tightly controlled during macrophage development; monocytes express truncated ZFR isoforms, while macrophages induce full-length ZFR to modulate macrophage-specific alternative splicing...
March 20, 2018: Nature Communications
Jeffrey S Mugridge, Ryan W Tibble, Marcin Ziemniak, Jacek Jemielity, John D Gross
The conserved decapping enzyme Dcp2 recognizes and removes the 5' eukaryotic cap from mRNA transcripts in a critical step of many cellular RNA decay pathways. Dcp2 is a dynamic enzyme that functions in concert with the essential activator Dcp1 and a diverse set of coactivators to selectively and efficiently decap target mRNAs in the cell. Here we present a 2.84 Å crystal structure of K. lactis Dcp1-Dcp2 in complex with coactivators Edc1 and Edc3, and with substrate analog bound to the Dcp2 active site. Our structure shows how Dcp2 recognizes cap substrate in the catalytically active conformation of the enzyme, and how coactivator Edc1 forms a three-way interface that bridges the domains of Dcp2 to consolidate the active conformation...
March 20, 2018: Nature Communications
Cyril Pottier, Evadnie Rampersaud, Matt Baker, Gang Wu, Joanne Wuu, Jacob L McCauley, Stephan Zuchner, Rebecca Schule, Christin Bermudez, Sumaira Hussain, Anne Cooley, Marielle Wallace, Jinghui Zhang, J Paul Taylor, Michael Benatar, Rosa Rademakers
Homozygous loss-of-function mutations in optineurin (OPTN) are a rare cause of amyotrophic lateral sclerosis (ALS), whereas heterozygous loss-of-function mutations have been suggested to increase ALS disease risk. We report a patient with ALS and frontotemporal dementia (FTD) from the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium carrying compound heterozygous loss-of-function variants in OPTN. Quantitative real-time mRNA expression analyses revealed a 75-80% reduction in OPTN expression in blood in the OPTN carrier as compared to controls, suggesting at least partial nonsense-mediated decay of the mutant transcripts...
March 20, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Wolf Achim Hassenpflug, Tobias Obser, Julia Bode, Florian Oyen, Ulrich Budde, Sonja Schneppenheim, Reinhard Schneppenheim, Maria Alexandra Brehm
Upshaw-Schulman syndrome (USS) is caused by severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency due to homozygous or compound heterozygous mutations in the ADAMTS13 gene. Previous studies suggest three possible disease mechanisms: (1) reduced secretion of ADAMTS13 variants, (2) impaired proteolytic activity, (3) defective biosynthesis due to nonsense-mediated decay. Expression studies have failed to establish a clear genotype/phenotype correlation that could explain the significant variability in the age of onset and patients' clinical courses...
March 19, 2018: Thrombosis and Haemostasis
Ahoura Nozari, Ehsan Aghaei-Moghadam, Aliakbar Zeinaloo, Reza Mollazadeh, Mohammad-Taghi Majnoon, Afagh Alavi, Saghar Ghasemi Firouzabadi, Akbar Mohammadzadeh, Susan Banihashemi, Mehrnoosh Nikzaban, Hossein Najmabadi, Farkhondeh Behjati
Recent achievements in the genetic diagnosis of Dilated Cardiomyopathy (DCM) have disclosed rare variants in numerous genes encoding different types of myocardial proteins. However, the causative gene underlying the pathogenesis of about 60% of familial cases with DCM has not been identified. One novel gene introduced in 2016 for cardiac-restricted DCM is FLNC. In this study, we applied Whole Exome Sequencing (WES) and bioinformatics-based methods to a member of an extended non-consanguineous family with DCM history accompanied with fatal arrhythmia in at least four consecutive generations...
March 15, 2018: Gene
Chun Wang, Susan Hockerman, E Jon Jacobsen, Yael Alippe, Shaun R Selness, Heidi R Hope, Jeffrey L Hirsch, Stephen J Mnich, Matthew J Saabye, William F Hood, Sheri L Bonar, Yousef Abu-Amer, Ariela Haimovich, Hal M Hoffman, Joseph B Monahan, Gabriel Mbalaviele
p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2...
March 16, 2018: Journal of Experimental Medicine
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