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1 Ribosomal Frameshift Signal of SARS-Cov-2
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.13.991083; this version posted March 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2 Jamie A. Kelly and Jonathan D. Dinman* Department of Cell Biology and Molecular Genetics, University of Maryland, College Park MD 20742 *Corresponding author: Jonathan D. Dinman E-mail: [email protected] Running title: Frameshifting in SARS-CoV-2 Keywords: COVID-19, coronavirus, programmed -1 ribosomal frameshifting (-1 PRF), translation, RNA, structure, virus, (+) ssRNA 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.13.991083; this version posted March 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract. Introduction 17 years after the SARS-CoV epidemic, the SARS-CoV2, the etiological agent of COVID- world is facing the COVID-19 pandemic. 19, is a member of the coronavirus family (1). COVID-19 is caused by a coronavirus named Coronaviruses have (+) ssRNA genomes that SARS-CoV-2. Given the most optimistic harbor two long open reading frames (ORF) projections estimating that it will take more than which occupy the 5’ ~ two-thirds of the genomic a year to develop a vaccine, our best short term RNA (ORF1 and ORF2), followed by several strategy may lie in identifying virus-specific ORFs that are expressed late in the viral targets for small molecule interventions. -
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. -
Lin28b and Mir-142-3P Regulate Neuronal Differentiation by Modulating Staufen1 Expression
Cell Death and Differentiation (2018) 25, 432–443 & 2018 ADMC Associazione Differenziamento e Morte Cellulare All rights reserved 1350-9047/18 www.nature.com/cdd Lin28B and miR-142-3p regulate neuronal differentiation by modulating Staufen1 expression Younseo Oh1,5, Jungyun Park1,5, Jin-Il Kim1, Mi-Yoon Chang2, Sang-Hun Lee3, Youl-Hee Cho*,4 and Jungwook Hwang*,1,4 Staufen1 (STAU1) and Lin28B are RNA-binding proteins that are involved in neuronal differentiation as a function of post- transcriptional regulation. STAU1 triggers post-transcriptional regulation, including mRNA export, mRNA relocation, translation and mRNA decay. Lin28B also has multiple functions in miRNA biogenesis and the regulation of translation. Here, we examined the connection between STAU1 and Lin28B and found that Lin28B regulates the abundance of STAU1 mRNA via miRNA maturation. Decreases in the expression of both STAU1 and Lin28B were observed during neuronal differentiation. Depletion of STAU1 or Lin28B inhibited neuronal differentiation, and overexpression of STAU1 or Lin28B enhanced neuronal differentiation. Interestingly, the stability of STAU1 mRNA was modulated by miR-142-3p, whose maturation was regulated by Lin28B. Thus, miR-142-3p expression increased as Lin28B expression decreased during differentiation, leading to the reduction of STAU1 expression. The transcriptome from Staufen-mediated mRNA decay (SMD) targets during differentiation was analyzed, confirming that STAU1 was a key factor in neuronal differentiation. In support of this finding, regulation of STAU1 expression in mouse neural precursor cells had the same effects on neuronal differentiation as it did in human neuroblastoma cells. These results revealed the collaboration of two RNA-binding proteins, STAU1 and Lin28B, as a regulatory mechanism in neuronal differentiation. -
Fall 2016 Is Available in the Laboratory of Dr
RNA Society Newsletter Aug 2016 From the Desk of the President, Sarah Woodson Greetings to all! I always enjoy attending the annual meetings of the RNA Society, but this year’s meeting in Kyoto was a standout in my opinion. This marked the second time that the RNA meeting has been held in Kyoto as a joint meeting with the RNA Society of Japan. (The first time was in 2011). Particular thanks go to the local organizers Mikiko Siomi and Tom Suzuki who took care of many logistical details, and to all of the organizers, Mikiko, Tom, Utz Fischer, Wendy Gilbert, David Lilley and Erik Sontheimer, for putting together a truly exciting and stimulating scientific program. Of course, the real excitement in the annual RNA meetings comes from all of you who give the talks and present the posters. I always enjoy meeting old friends and colleagues, but the many new participants in this year’s meeting particularly encouraged me. (Continued on p2) In this issue : Desk of the President, Sarah Woodson 1 Highlights of RNA 2016 : Kyoto Japan 4 Annual Society Award Winners 4 Jr Scientist activities 9 Mentor Mentee Lunch 10 New initiatives 12 Desk of our CEO, James McSwiggen 15 New Volunteer Opportunities 16 Chair, Meetings Committee, Benoit Chabot 17 Desk of the Membership Chair, Kristian Baker 18 Thank you Volunteers! 20 Meeting Reports: RNA Sponsored Meetings 22 Upcoming Meetings of Interest 27 Employment 31 1 Although the graceful city of Kyoto and its cultural months. First, in May 2016, the RNA journal treasures beckoned from just beyond the convention instituted a uniform price for manuscript publication hall, the meeting itself held more than enough (see p 12) that simplifies the calculation of author excitement to keep ones attention! Both the quality fees and facilitates the use of color figures to and the “polish” of the scientific presentations were convey scientific information. -
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. -
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 -
Mrna Stem-Loops Can Pause the Ribosome by Hindering A-Site Trna
RESEARCH ARTICLE mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding Chen Bao1†, Sarah Loerch2†, Clarence Ling1, Andrei A Korostelev3,4, Nikolaus Grigorieff2,4*, Dmitri N Ermolenko1* 1Department of Biochemistry and Biophysics at School of Medicine and Dentistry and Center for RNA Biology, University of Rochester, Rochester, United States; 2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States; 3Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States; 4RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States Abstract Although the elongating ribosome is an efficient helicase, certain mRNA stem-loop structures are known to impede ribosome movement along mRNA and stimulate programmed ribosome frameshifting via mechanisms that are not well understood. Using biochemical and single- molecule Fo¨ rster resonance energy transfer (smFRET) experiments, we studied how frameshift- inducing stem-loops from E. coli dnaX mRNA and the gag-pol transcript of Human Immunodeficiency Virus (HIV) perturb translation elongation. We find that upon encountering the ribosome, the stem-loops strongly inhibit A-site tRNA binding and ribosome intersubunit rotation *For correspondence: that accompanies translation elongation. Electron cryo-microscopy (cryo-EM) reveals that the HIV [email protected] (NG); stem-loop docks into the A site of the ribosome. Our results suggest that mRNA stem-loops can Dmitri_Ermolenko@urmc. transiently escape the ribosome helicase by binding to the A site. Thus, the stem-loops can rochester.edu (DNE) modulate gene expression by sterically hindering tRNA binding and inhibiting translation †These authors contributed elongation. equally to this work Competing interest: See page 22 Introduction Funding: See page 22 During translation elongation, the ribosome moves along mRNA in a codon-by-codon manner while Received: 06 February 2020 the mRNA is threaded through the mRNA channel of the small ribosomal subunit. -
HIV-1 Virus Cycle Replication: a Review of RNA Polymerase II Transcription, Alternative Splicing and Protein Synthesis Corresponding Autor
HIV-1 virus cycle replication: a review of RNA polymerase II transcription, alternative splicing and protein synthesis Correspondingautor: MiguelRamos-Pascual Abstract HIV virus replication is a time-related process that includes attachment to host cell and fusion, reverse transcription, integration on host cell DNA, transcription and splicing, multiple mRNA transport, protein synthesis, budding and maturation. Focusing on the core steps, RNA polymerase II transcripts in an early stage pre-mRNA containing regulator proteins (i.e nef,tat,rev,vif,vpr,vpu), which are completely spliced by the spliceosome complex (0.9kb and 1.8kb) and exported to the ribosome for protein synthesis. These splicing and export processes are regulated by tat protein, which binds on Trans-activation response (TAR) element, and by rev protein, which binds to the Rev-responsive Element (RRE). As long as these regulators are synthesized, splicing is progressively inhibited (from 4.0kb to 9.0kb) and mRNAs are translated into structural and enzymatic proteins (env, gag-pol). During this RNAPII scanning and splicing, around 40 different multi-cystronic mRNA have been produced. Long-read sequencing has been applied to the HIV-1 virus genome (type HXB2CG) with the HIV.pro software, a fortran 90 code for simulating the virus replication cycle, specially RNAPII transcription, exon/intron splicing and ribosome protein synthesis, including the frameshift at gag/pol gene and the ribosome pause at env gene. All HIV-1 virus proteins have been identified as far as other ORFs. As observed, tat/rev protein regulators have different length depending on the splicing cleavage site: tat protein varies from 224aa to a final state of 72aa, whereas rev protein from 25aa to 27aa, with a maximum of 119aa. -
Biological Chemistry 2011 Newsletter a Letter from the Chair : Dr
0.2 -1 k obs (s ) 0.1 EFlred - 0 0 ESQ O2 EFlox + H2O 2 0.4 00 0.6 0 0.2 1 O 2 [O 2] (mM)mM .22 EFlred 0 ESQ O - EFl + H O 2 ox 2 2 10 O 2 .18 0 EFlred - ESQ O EFl + H2O 2 2 ox 0 4 1 O 5 .1 2 4 0 EFlred - 1 ESQ O2 EFlox + H2O 2 1 0. 0. O2 BiologicalNewsletter Chemistry 2011 A Letter from the Chair : Dr. William L. Smith Greetings from Ann Arbor to Friends, Colleagues, and Graduates laboratory are famously I’ll begin like I do most successful in developing years with an update on algorithms for protein the state of the Depart- structure predictions. He and his group were ment. As a reminder, Biological Chemistry is ranked No. 1 in both pro- one of six basic science departments in a medical tein structure and function prediction among more school with now 26 different departments and two than 200 groups in the most recent international new ones (Cardiovascular Surgery and Bioinformat- competition (http://zhanglab.ccmb.med.umich.edu/). ics) due to be instituted soon. We currently have 47 Dr. Daniel Southworth has recently been appointed faculty with appointments in Biological Chemistry to a tenure track appointment as an Assistant Profes- all of whom have shared responsibilities for teaching sor in Biological Chemistry with a research track ap- graduate, medical and undergraduate students. The pointment in the Life Sciences Institute. Most recent- Department averages about 35 graduate students in ly, Dan received his Ph.D.