Lin28b and Mir-142-3P Regulate Neuronal Differentiation by Modulating Staufen1 Expression
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The Ribosome As a Regulator of Mrna Decay
www.nature.com/cr www.cell-research.com RESEARCH HIGHLIGHT Make or break: the ribosome as a regulator of mRNA decay Anthony J. Veltri1, Karole N. D’Orazio1 and Rachel Green 1 Cell Research (2020) 30:195–196; https://doi.org/10.1038/s41422-019-0271-3 Cells regulate α- and β-tubulin levels through a negative present. To address this, the authors mixed pre-formed feedback loop which degrades tubulin mRNA upon detection TTC5–tubulin RNCs containing crosslinker with lysates from of excess free tubulin protein. In a recent study in Science, Lin colchicine-treated or colchicine-untreated TTC5-knockout cells et al. discover a role for a novel factor, TTC5, in recognizing (either having or lacking abundant free tubulin, respectively). the N-terminal motif of tubulins as they emerge from the After irradiation, TTC5 only crosslinked to the RNC in lysates ribosome and in signaling co-translational mRNA decay. from cells that had previously been treated with colchicine; Cells use translation-coupled mRNA decay for both quality these data suggested to the authors that some other (unknown) control and general regulation of mRNA levels. A variety of known factor may prevent TTC5 from binding under conditions of low quality control pathways including Nonsense Mediated Decay free tubulin. (NMD), No-Go Decay (NGD), and Non-Stop Decay (NSD) specifi- What are likely possibilities for how such coupling between cally detect and degrade mRNAs encoding potentially toxic translation and mRNA decay might occur? One example to protein fragments or sequences which cause ribosomes to consider is that of mRNA surveillance where extensive studies in translate poorly or stall.1 More generally, canonical mRNA yeast have identified a large group of proteins that recognize degradation is broadly thought to be translation dependent, and resolve stalled RNCs found on problematic mRNAs and 1234567890();,: though the mechanisms that drive these events are not target those mRNAs for decay. -
Ribosomes Slide on Lysine-Encoding Homopolymeric a Stretches
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref RESEARCH ARTICLE elifesciences.org Ribosomes slide on lysine-encoding homopolymeric A stretches Kristin S Koutmou1, Anthony P Schuller1, Julie L Brunelle1,2, Aditya Radhakrishnan1, Sergej Djuranovic3, Rachel Green1,2* 1Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, United States; 2Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States; 3Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, United States Abstract Protein output from synonymous codons is thought to be equivalent if appropriate tRNAs are sufficiently abundant. Here we show that mRNAs encoding iterated lysine codons, AAA or AAG, differentially impact protein synthesis: insertion of iterated AAA codons into an ORF diminishes protein expression more than insertion of synonymous AAG codons. Kinetic studies in E. coli reveal that differential protein production results from pausing on consecutive AAA-lysines followed by ribosome sliding on homopolymeric A sequence. Translation in a cell-free expression system demonstrates that diminished output from AAA-codon-containing reporters results from premature translation termination on out of frame stop codons following ribosome sliding. In eukaryotes, these premature termination events target the mRNAs for Nonsense-Mediated-Decay (NMD). The finding that ribosomes slide on homopolymeric A sequences explains bioinformatic analyses indicating that consecutive AAA codons are under-represented in gene-coding sequences. Ribosome ‘sliding’ represents an unexpected type of ribosome movement possible during translation. DOI: 10.7554/eLife.05534.001 *For correspondence: ragreen@ Introduction jhmi.edu Messenger RNA (mRNA) transcripts can contain errors that result in the production of incorrect protein products. -
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Staufen2 functions in Staufen1-mediated mRNA decay INAUGURAL ARTICLE by binding to itself and its paralog and promoting UPF1 helicase but not ATPase activity Eonyoung Parka,b, Michael L. Gleghorna,b, and Lynne E. Maquata,b,1 aDepartment of Biochemistry and Biophysics, School of Medicine and Dentistry, and bCenter for RNA Biology, University of Rochester, Rochester, NY 14642 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2011. Edited by Michael R. Botchan, University of California, Berkeley, CA, and approved November 16, 2012 (received for review August 3, 2012) Staufen (STAU)1-mediated mRNA decay (SMD) is a posttranscrip- harbor a STAU1-binding site (SBS) downstream of their normal tional regulatory mechanism in mammals that degrades mRNAs termination codon in a pathway called STAU1-mediated mRNA harboring a STAU1-binding site (SBS) in their 3′-untranslated regions decay or SMD (13, 14), and work published by others indicates (3′ UTRs). We show that SMD involves not only STAU1 but also its that SMD does not involve STAU2 (3, 15). paralog STAU2. STAU2, like STAU1, is a double-stranded RNA-binding According to our current model for SMD, when translation protein that interacts directly with the ATP-dependent RNA helicase terminates upstream of an SBS, recruitment of the nonsense-me- diated mRNA decay (NMD) factor UPF1 to SBS-bound STAU1 up-frameshift 1 (UPF1) to reduce the half-life of SMD targets that form fl an SBS by either intramolecular or intermolecular base-pairing. Com- triggers mRNA decay. SMD in uences a number of cellular pro- pared with STAU1, STAU2 binds ∼10-foldmoreUPF1and∼two- to cesses, including the differentiation of mouse C2C12 myoblasts to myotubes (16), the motility of human HaCaT keratinocytes (17), fivefold more of those SBS-containing mRNAs that were tested, and it and the differentiation of mouse 3T3-L1 preadipocytes to adipo- comparably promotes UPF1 helicase activity, which is critical for SMD. -
Staufen 1 Amplifies Pro-Apoptotic Activation of the Unfolded Protein
bioRxiv preprint doi: https://doi.org/10.1101/820225; this version posted October 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Staufen 1 amplifies pro-apoptotic activation of the unfolded protein response Mandi Gandelman, Warunee Dansithong, Karla P Figueroa, Sharan Paul, Daniel R Scoles, Stefan M Pulst. Author affiliation and address: Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, Utah 84132, USA Corresponding author: Stefan M. Pulst [email protected] Running title: STAU1 amplifies apoptosis Abstract Staufen-1 (STAU1) is an RNA binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP) or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the Unfolded Protein Response (UPR), a common feature among the neurodegenerative diseases where STAU1 is increased, and is directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK-CHOP pathway. STAU1 levels increased in response to multiple ER stressors and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK-CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1-/- mice showed reduced UPR and apoptosis when challenged with thapsigargin. -
Mrna Turnover Philip Mitchell* and David Tollervey†
320 mRNA turnover Philip Mitchell* and David Tollervey† Nuclear RNA-binding proteins can record pre-mRNA are cotransported to the cytoplasm with the mRNP. These processing events in the structure of messenger proteins may preserve a record of the nuclear history of the ribonucleoprotein particles (mRNPs). During initial rounds of pre-mRNA in the cytoplasmic mRNP structure. This infor- translation, the mature mRNP structure is established and is mation can strongly influence the cytoplasmic fate of the monitored by mRNA surveillance systems. Competition for the mRNA and is used by mRNA surveillance systems that act cap structure links translation and subsequent mRNA as a checkpoint of mRNP integrity, particularly in the identi- degradation, which may also involve multiple deadenylases. fication of premature translation termination codons (PTCs). Addresses Cotransport of nuclear mRNA-binding proteins with mRNA Wellcome Trust Centre for Cell Biology, ICMB, University of Edinburgh, from the nucleus to the cytoplasm (nucleocytoplasmic shut- Kings’ Buildings, Edinburgh EH9 3JR, UK tling) was first observed for the heterogeneous nuclear *e-mail: [email protected] ribonucleoprotein (hnRNP) proteins. Some hnRNP proteins †e-mail: [email protected] are stripped from the mRNA at export [1], but hnRNP A1, Current Opinion in Cell Biology 2001, 13:320–325 A2, E, I and K are all exported (see [2]). Although roles for 0955-0674/01/$ — see front matter these hnRNP proteins in transport and translation have been © 2001 Elsevier Science Ltd. All rights reserved. reported [3•,4•], their affects on mRNA stability have been little studied. More is known about hnRNP D/AUF1 and Abbreviations AREs AU-rich sequence elements another nuclear RNA-binding protein, HuR, which act CBC cap-binding complex antagonistically to modulate the stability of a range of DAN deadenylating nuclease mRNAs containing AU-rich sequence elements (AREs) DSEs downstream sequence elements (reviewed in [2]). -
Nonsense Mediated Mrna Decay As a Tool for Gene Therapy and the Role of Human DIS3L2 in Transcript Degradation
UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL mRNA Metabolism: Nonsense Mediated mRNA Decay as a Tool for Gene Therapy and the Role of Human DIS3L2 in Transcript Degradation Mestrado em Biologia Humana e Ambiente Gerson Leonel Asper Amaral Dissertação orientada por: Doutora Luísa Romão Professora Doutora Deodália Dias 2016 II UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA ANIMAL mRNA Metabolism: Nonsense Mediated mRNA Decay as a Tool for Gene Therapy and the Role of Human DIS3L2 in Transcript Degradation Mestrado em Biologia Humana e Ambiente Gerson Leonel Asper Amaral Dissertação orientada por: Doutora Luísa Romão (Instituto Nacional de Saúde Dr. Ricardo Jorge) Professora Doutora Deodália Dias (Departamento de Biologia Animal, Faculdade de Ciências da Universidade de Lisboa) 2016 III IV “It is finished.” – Jesus Christ (The Bible, John 19:30) V VI ACKNOWLEDGEMENTS _______________________________________________________________________ This dissertation is the result of the very hard work, patience and resources from a lot of people. They were instrumental in the accomplishment of this project, be it through their knowledge, plain lab work, their friendship, guidance, support or sheer trust. I am sincerely thankful that all of you made part of my life at least for this year, because without you this would never see the light of day and would remain in the darkness of night. Clichéd poetry aside, honestly, thank you all. I want to start by thanking my main advisor, Dr. Luísa Romão, for accepting me into her brilliant lab and trusting me and my work. Thank you for sharing your vast knowledge with me, helping me, guiding me, being patient and calling my attention to my mistakes, all this without ever stopping from being pleasant! I feel so honoured and thankful. -
Staufen 1 Does Not Play a Role in NPC Asymmetric Divisions but Regulates Cellular Positioning During Corticogenesis
Staufen 1 does not play a role in NPC asymmetric divisions but regulates cellular positioning during corticogenesis by Christopher Kuc A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Master of Science in Molecular and Cellular Biology Guelph, Ontario, Canada © Christopher Kuc, September 2018 ABSTRACT INVESTIGATING THE ROLE OF STAUFEN1 IN ASYMMETRIC NEURAL PRECURSOR CELL DIVISIONS IN THE DEVELOPING CEREBRAL CORTEX Christopher Kuc Advisors: Dr. John Vessey University of Guelph, 2018 Cerebral cortex development relies on asymmetric divisions of neural precursor cells (NPCs) to produce a recurring NPC and a differentiated neuron. Asymmetric divisions are promoted by the differential localization of cell fate determinants between daughter cells. Staufen 1 (Stau1) is an RNA-binding protein known to localize mRNA in mature hippocampal neurons. However, its expression pattern and role in the developing mammalian cortex remains unknown. In this study, Stau1 mRNA and protein were found to be expressed in all cells examined and was temporally and spatially characterized across development. Upon shRNA-mediated knockdown of Stau1 in primary cortical cultures, NPCs retained the ability to self-renew and generate neurons despite the loss of Stau1 expression. This said, in vivo knockdown of Stau1 demonstrated that it may play a role in anchoring NPCs to the ventricular zone during cortical development. ACKNOWLEDGMENTS I would first like to thank my advisor Dr. John Vessey. Throughout these 2 years, you have provided me with an invaluable opportunity and played an instrumental role in shaping me as a scientist. The guidance, support and expertise you have provided me will be always appreciated and never forgotten. -
Mrna Surveillance in Eukaryotes: Kinetic Proofreading of Proper Translation Termination As Assessed by Mrnp Domain Organization?
Downloaded from rnajournal.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press RNA (1999), 5:711–719+ Cambridge University Press+ Printed in the USA+ Copyright © 1999 RNA Society+ REVIEW mRNA surveillance in eukaryotes: Kinetic proofreading of proper translation termination as assessed by mRNP domain organization? PATRICIA HILLEREN and ROY PARKER Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of Arizona, Tucson, Arizona 85721, USA ABSTRACT In the last few years it has become clear that a conserved mRNA degradation system, referred to as mRNA surveil- lance, exists in eukaryotic cells to degrade aberrant mRNAs. This process plays an important role in checking that mRNAs have been properly synthesized and functions, at least in part, to increase the fidelity of gene expression by degrading aberrant mRNAs that, if translated, would produce truncated proteins. A critical issue is how normal and aberrant mRNAs are distinguished and how that distinction leads to differences in mRNA stability. Recent results suggest a model with three main points. First, mRNPs have a domain organization that is, in part, a reflection of the completion of nuclear pre-mRNA processing events. Second, the critical aspect of distinguishing a normal from an aberrant mRNA is the environment of the translation termination codon as determined by the organization of the mRNP domains. Third, the cell distinguishes proper from improper termination through an internal clock that is the rate of ATP hydrolysis by Upf1p. If termination is completed before ATP hydrolysis, the mRNA is protected from mRNA degradation. Conversely, if termination is slow, then ATP hydrolysis and a structural rearrangement occurs before termination is completed, which affects the fate of the terminating ribosome in a manner that fails to stabilize the mRNA. -
The Role of DIS3L2 in the Degradation of the Uridylated RNA Species in Humans
MASARYK UNIVERSITY Faculty of Science National Center for Biomedical Research Dmytro Ustianenko The role of DIS3L2 in the degradation of the uridylated RNA species in humans Ph.D. THESIS SUPERVISOR doc. Mgr. ŠTĚPÁNKA VAŇÁČOVÁ, Ph.D. BRNO, 2014 _______________________________ Cover: A schematic representation of the RNA degradation process which oc- curs in the cytoplasm. Copyright © 2014 Dmytro Ustianenko, Masaryk University, All rights reserved. _______________________________ Copyright © Dmytro Ustianenko, Masaryk University Bibliographic entry Author: Mgr. Dmytro Ustianenko Faculty of Science, Masaryk University National Centre for Biomolecular Research Central European Institute of Technology Title of Dissertation: The role of DIS3L2 in the degradation of the uridylat- ed RNA species in humans. Degree Programme: Biochemistry Field of Study: Biomolecular chemistry Supervisor: Doc. Mgr. Štěpánka Vaňáčová, Ph.D. Academic Year: 2014 Number of Pages: 131 Keywords: RNA degradation, DIS3L2, uridylation, humans, miRNA, let-7 Bibliografický záznam Autor: Mgr. Dmytro Ustianenko Přírodovědecká fakulta, Masarykova univerzita Národní centrum pro výzkum biomolekul Středoevropský technologický institut Název práce: The role of DIS3L2 in the degradation of the uridylat- ed RNA species in humans. Studijní program: Biochemie Studijní obor: Biomolekulární chemie Školitel: doc. Mgr. Štěpánka Vaňáčová, Ph.D. Akademický rok: 2014 Počet stran: 131 Klíčová slova: RNA degradace, DIS3L2, uridylace, mikro RNA, let-7 Acknowledgements I would like to thank to all the people who have contributed to this work. Foremost I would like to thank my supervisor Stepanka Vanacova for her enthusiasm, support and patience though all of my studies. I would like to acknowledge the members of the RNA processing and degradation group for their support and help in achieving this goal. -
Role of Mrna Surveillance Pathways During Oxidative Stress in Saccharomyces Cerevisiae a Thesis Submitted to the University of M
Role of mRNA surveillance pathways during oxidative stress in Saccharomyces Cerevisiae A thesis submitted to The University of Manchester for the degree of DOCTOR OF PHILOSOPHY in the Faculty of Biology, Medicine and Health 2017 NUR HIDAYAH JAMAR SCHOOL OF BIOLOGICAL SCIENCES 1 Table of Content Table of Content 2 List of Figures 9 List of Tables 12 Declaration 13 Copyright statement 13 Communications 14 Publication 14 Contributor’s acknowledgment 15 Acknowledgments 16 List of abbreviations 17 Abstract 21 1.0 introduction 23 1.1 Generation of reactive oxygen species (ROS) 23 1.2 Sources of ROS and commonly used ROS compounds 25 1.3 What happens when cells cannot handle oxidative stress? 26 1.3.1 Lipid peroxidation 27 1.3.2 Protein oxidation 29 1.3.3 Oxidatively damaged nucleic acids (DNA and RNA) 30 1.4.Transcriptional responses of S. cerevisiae during oxidative stress 31 conditions 1.4.1 Regulation of gene expression by Yap1 32 2 1.4.2 Modulation of the general stress response by MSN2/MSN4 33 1.5 Translational responses of S. cerevisiae to oxidative stress conditions 34 1.5.1 Overview of protein synthesis 34 1.5.1.1 Translation initiation 34 1.5.1.2 Translation elongation 37 1.5.1.3 Translation termination 39 1.5.2 Regulation of translation initiation during oxidative stress in S. 39 cerevisiae 1.5.2.1 Regulation of TC by eIF2α 41 1.5.2.2 Regulation of mRNA-specific translational control via Gcn4 43 1.6 Cytoplasmic mRNA degradation in S. cerevisiae 43 1.6.1 Normal mRNA degradation 44 1.6.2 Specialized mRNA quality control mechanisms 47 -
Non-Canonical Immune Response to the Inhibition of DNA Methylation Via Stabilization Of
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.21.163857; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs Yongsuk Ku1,6, Joo-Hwan Park2,3,6, Ryeongeun Cho1,6, Yongki Lee1, Hyoung-Min Park4, MinA Kim1, Kyunghoon Hur1, Soo Young Byun5, Jun Liu2,3, David Shum5, Dong-Yeop Shin2,3, Youngil Koh2,3, Je-Yoel Cho4, Sung-Soo Yoon2,3, Junshik Hong2,3*, Yoosik Kim1* 1Department of Chemical and Biomolecular Engineering and KAIST Institute for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea 3Cancer Research Institute, Seoul National University Hospital, Seoul, Korea 4Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea 5Screening Discovery Platform, Translation Research Division, Institut Pasteur Korea, Seongnam, Gyeonggi, Korea. 6These authors contributed equally *To whom correspondence should be addressed: [email protected] (Y.K). Correspondence may also be addressed to: [email protected] (J. H). 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.21.163857; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. -
Novel Autoregulatory Cases of Alternative Splicing Coupled with Nonsense-Mediated Mrna Decay
bioRxiv preprint doi: https://doi.org/10.1101/464404; this version posted November 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Novel autoregulatory cases of alternative splicing coupled with nonsense-mediated mRNA decay Dmitri Pervouchine 1,2,*, Yaroslav Popov 2, Andy Berry 3, Beatrice Borsari 4, Adam Frankish 3, Roderic Guig´o 4 1 Skolkovo Institute of Science and Technology, 3 Nobel st, Moscow 143026, Russia; 2 Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskiye Gory 1-73, 119234 Moscow, Russia; 3 The European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SA Hinxton, Cambridge, United Kingdom; 4 Center for Genomic Regulation and UPF, Dr. Aiguader 88, Barcelona 08003, Spain * The correspondence should be addressed to [email protected] Abstract Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades 1 transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their 2 expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative 3 splicing to introduce a PTC. We present a bioinformatic framework to identify novel such autoregulatory 4 feedback loops by combining eCLIP assays for a large panel of RBPs with the data on shRNA inactivation 5 of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq. We show that RBPs frequently bind 6 their own pre-mRNAs and respond prominently to NMD pathway disruption. Poison and essential exons, 7 i.e., exons that trigger NMD when included in the mRNA or skipped, respectively, respond oppositely to the 8 inactivation of NMD pathway and to the depletion of their host genes, which allows identification of novel 9 autoregulatory mechanisms for a number of human RBPs.