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Stress-mediated effects on ribosome functions and translation control

English title Stress-mediated effects on ribosome functions and translation control
Applicant Polacek Norbert
Number 166527
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Molecular Biology
Start/End 01.07.2016 - 31.10.2019
Approved amount 620'000.00
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All Disciplines (3)

Discipline
Molecular Biology
Biochemistry
Organic Chemistry

Keywords (7)

rRNA; ribosome; non-coding RNAs; translation; RNA biology; translation regulation; nucleotide analog interference

Lay Summary (German)

Lead
Das Ribosom, ein universell konserviertes multifunktionales RNA-Protein Enzym, ist für die Proteinsynthese (= Translation) in allen lebenden Zellen zuständig. Die wesentliche Rolle des Ribosoms für die Zelle ist auch daran zu erkennen, dass es Hauptangriffspunkt vieler klinisch relevanter Antibiotika ist und eine zentrale Schaltstelle der Stressantwort darstellt.
Lay summary

Inhalt und Ziel des Forschungsprojektes

Ziel dieses Forschungsprojektes ist es, (1) die Auswirkung von oxidativem Stress auf die Funktion und Struktur der bakteriellen Ribosoms zu untersuchen, sowie (2) das regulatorische Potenzial von Stress-induzierten nicht-Protein-kodierenden RNAs (ncRNAs) der Bäckerhefe zu untersuchen. Regulation der Proteinsynthese ermöglicht es Zellen, schnell und effizient auf geänderte Umweltbedingungen reagieren zu können. Um diese Ziele erreichen zu können kommen neu entwickelte biochemische, molekular- und zellbiologische Methoden zum Einsatz.  

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Im Rahmen dieses Grundlagenforschungsprojekts werden wir die molekularen Mechanismen der zellulären Stressantwort auf der Ebene der Proteinbiosynthese erforschen. Inadäquate Stressantwort und eine damit einhergehende ungeeignete Regulation der Proteinsynthese ist mit mehreren menschlichen Erkrankungen in Verbindung gebracht worden (z.B. Alzheimer, Krebs). Ein besseres molekulares Verständnis der Stress-bedingten Zellantwort ist daher Voraussetzung für ein potentielles therapeutisches Eingreifen in die Translationskontrolle.

Direct link to Lay Summary Last update: 12.05.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
A tRNA half modulates translation as stress response in Trypanosoma brucei
Fricker Roger, Brogli Rebecca, Luidalepp Hannes, Wyss Leander, Fasnacht Michel, Joss Oliver, Zywicki Marek, Helm Mark, Schneider André, Cristodero Marina, Polacek Norbert (2019), A tRNA half modulates translation as stress response in Trypanosoma brucei, in Nature Communications, 10(1), 118-118.
tRNA Biology in Trypanosomes
Shikha Shikha, Brogli Rebecca, Schneider André, Polacek Norbert (2019), tRNA Biology in Trypanosomes, in CHIMIA International Journal for Chemistry, 73(5), 395-405.
Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth
HeissenbergerClemens, LiendlLisa, NagelreiterFabian, GonskikhYulia, YangGuohuan, StelzerElena, KrammerTeresa, MicutkovaLucia, VogtStefan, KreilDavid, SekotGerhard, SienaEmilio, PoserIna, HarreitherEva, LinderAngela, EhretViktoria, HelbichThomas, Grillari-VoglauerRegina, Jansen-DürrPidder, KosMartin, PolacekNorbert, GrillariJohannes, SchossererMarkus (2019), Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth, in Nucleic Acids Research, 1043.
mRNA-specific translation regulation by a ribosome-associated ncRNA in Haloferax volcanii
Wyss Leander, Waser Melanie, Gebetsberger Jennifer, Zywicki Marek, Polacek Norbert (2018), mRNA-specific translation regulation by a ribosome-associated ncRNA in Haloferax volcanii, in Scientific Reports, 8(1), 12502-12502.
Oxidative stress damages rRNA inside the ribosome and differentially affects the catalytic center
Willi Jessica, Küpfer Pascal, Evéquoz Damien, Fernandez Guillermo, Katz Assaf, Leumann Christian, Polacek Norbert (2018), Oxidative stress damages rRNA inside the ribosome and differentially affects the catalytic center, in Nucleic Acids Research, 46(4), 1945-1957.
Atomic mutagenesis of stop codon nucleotides reveals the chemical prerequisites for release factor-mediated peptide release
Hoernes Thomas, Clementi Nina, Juen Michael, Shi Xinying, Faserl Klaus, Willi Jessica, Gasser Catherina, Kreutz Christoph, Joseph Simpson, Lindner Herbert, Hüttenhofer Alexander, Erlacher Matthias (2018), Atomic mutagenesis of stop codon nucleotides reveals the chemical prerequisites for release factor-mediated peptide release, in Proceedings of the National Academy of Sciences, E382.
Critical 23S rRNA interactions for macrolide-dependent ribosome stalling on the ErmCL nascent peptide chain
Koch Miriam, Willi Jessica, Pradère Ugo, Hall Jonathan, Polacek Norbert (2017), Critical 23S rRNA interactions for macrolide-dependent ribosome stalling on the ErmCL nascent peptide chain, in Nucleic Acids Research, 6717.
A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress.
Gebetsberger Jennifer, Wyss Leander, Mleczko Anna M, Reuther Julia, Polacek Norbert (2016), A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress., in RNA biology, 0-0.

Datasets

mRNA-specific translation regulation by a ribosome-associated ncRNA in Haloferax volcanii

Author Wyss, Leander; Waser, Melanie; Gebetsberger, Jennifer; Zywicki, Marek; Polacek, Norbert
Publication date 21.12.2018
Persistent Identifier (PID) 10.1038/s41598-018-30332-w
Repository European Nucleotide Archive


A tRNA half modulates translation as stress response in Trypanosoma brucei

Author Fricker, Roger; Brogli, Rebecca; Luidalepp, Hannes; Wyss, Leander; Fasnacht, Michel; Joss, Oliver; Zywicki, Marek; Helm, Mark; Schneider, André; Cristodero, Marina; Polacek, Norbert
Publication date 10.12.2019
Persistent Identifier (PID) 10.1038/s41467-018-07949-6
Repository European Nucleotide Archive


Collaboration

Group / person Country
Types of collaboration
Prof. Benoit Zuber Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christian Leumann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Patrick Limbach United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jonathan Hall Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Marek Zywicki Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
24th Annual Meeting of the RNA Society Poster Revealing where ribosomal RNA gets oxidized via Mass Spectrometry-generated maps 11.06.2019 Krakau, Poland Willi Jessica; Willi Jessica; Polacek Norbert;
24th Annual Meeting of the RNA Society Talk given at a conference Modulation of mammalian translation by the tRNAPro half 11.06.2019 Krakau, Poland Polacek Norbert; Gonskikh Yulia;
24th Annual Meeting of the RNA Society Poster A tRNA half modulates translation as stress response in Trypanosoma brucei 11.06.2019 Krakau, Poland Polacek Norbert;
Ribosome - Structure and Function 2019 Poster Mapping oxidation of the ribosomal RNA via Mass Spectrometry 06.01.2019 Merida, Mexico Polacek Norbert; Willi Jessica;
Ribosome - Structure and Function 2019 Poster Insights into function and processing of a ribosome-associated non-coding RNA in yeast 06.01.2019 Merida, Mexico Polacek Norbert; Reuther Julia; Schneider Lukas;
Ribosome - Structure and Function 2019 Talk given at a conference The multifaceted roles of ribosome-associated ncRNAs during translation control 06.01.2019 Merida, Mexico Schneider Lukas; Wyss Leander; Polacek Norbert; Gonskikh Yulia; Reuther Julia;
tRNA conference 2018 Poster Shortening of tRNAs as a mechanism of translational silencing during stress 23.09.2018 Strasbourg, France Polacek Norbert;
tRNA conference 2018 Talk given at a conference The multifaceted roles of ribosomeassociated tRNA-derived fragments during translation control 23.09.2018 Strasbourg, France Gonskikh Yulia; Polacek Norbert;
tRNA conference 2018 Poster A tRNA half modulates translation as stress response in Trypanosoma brucei 23.09.2018 Strasbourg, France Polacek Norbert;
tRNA conference 2018 Talk given at a conference Effects of the tRNAPro half on translation in mammalian cells 23.09.2018 Strasbourg, France Gonskikh Yulia; Polacek Norbert;
RiboClub 2017 Talk given at a conference The multifaceted roles of ribosome-associated ncRNAs (rancRNAs) 24.09.2017 Orford, Canada Reuther Julia; Schneider Lukas; Gonskikh Yulia; Wyss Leander; Polacek Norbert;
22nd Annual Meeting of the RNA Society Poster How Oxidation of the Ribosome’s Active Site Affects Translation 30.05.2017 Prag, Czech Republic Willi Jessica; Polacek Norbert;
22nd Annual Meeting of the RNA Society Talk given at a conference Fragmentation of tRNAs in Trypanosoma brucei during stress 30.05.2017 Prag, Czech Republic Polacek Norbert;
26th tRNA Conference Talk given at a conference The role of tRNA-derived fragments in stress response 05.09.2016 Jeju, Korean Republic (South Korea) Polacek Norbert;
26th tRNA Conference Poster Biology of tRNAs in Trypanosoma brucei during stress 04.09.2016 Jeju, Korean Republic (South Korea) Polacek Norbert;
EMBO Conference Ribosome – Structure and Function Talk given at a conference Ribosome-associated ncRNAs (rancRNAs): An emerging class of translation regulators 09.07.2016 Strasbourg, France Polacek Norbert;
EMBO Conference Ribosome – Structure and Function Poster Oxidized bases in the ribosome's peptidyl transferase center and their effects on translation 09.07.2016 Strasbourg, France Polacek Norbert; Willi Jessica;
EMBO Conference Ribosome – Structure and Function Poster An intergenic non-coding RNA targets and regulates the ribosome in H. volcanii 06.07.2016 Strasbourg, France Wyss Leander; Polacek Norbert;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Lehrerfortbildung für Chemie Gymnasiallehrer Talk 06.03.2017 Bern, Switzerland Polacek Norbert;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions BioChemie am Samstag: Vortrag an der Uni. Bern German-speaking Switzerland 2017
Talks/events/exhibitions Nacht der Forschung (an der Uni bern) German-speaking Switzerland 2017

Awards

Title Year
SNF Doc.mobility grant 2018

Associated projects

Number Title Start Funding scheme
188969 The stressed ribosome: from molecular characterization to cellular consequences 01.11.2019 Project funding (Div. I-III)
141735 NCCR RNA & disease: Understanding the role of RNA biology in disease mechanisms (phase I) 01.05.2014 National Centres of Competence in Research (NCCRs)
162559 The role of specialized ribosomes in stress resistance and healthy aging 01.02.2016 Project funding (Div. I-III)
143388 Molecular insight into ribosome functions and translation regulation 01.01.2013 Project funding (Div. I-III)
181745 Mapping oxidation of the ribosomal RNA via Mass Spectroscopy 01.07.2018 Doc.Mobility

Abstract

1.SUMMARYThe ribosome is the largest known RNA catalyst and is certainly one of the most central enzymes for cellular metabolism. Recent advances in the research field of protein biosynthesis suggest that the translation machinery serves as pivotal regulatory hub in protein homeostasis and stress response. While initially it was assumed that every ribosome in a cell or organism is identical in respect to its molecular composition and catalytic performance, a growing body of evidence argues against this view. It has been shown that translation in general and the ribosome in particular has to rapidly adapt to external signals. Especially during stress response the rate of protein biosynthesis has to be tightly adjusted in order not to waste precious cellular energy and to allow stress-response adaptation networks to be established. Failure of the translation apparatus to adequately respond to challenging environmental condition has been amply implied in cell death and disease. In this proposal we want to address two fundamental questions: (i)What are the consequences of oxidative stress on the structure and function of the ribosome?(ii)How do small ribosome-associated non-coding RNAs regulate translation?To gain insight into the consequences of oxidative stress on the ribosome, we will apply an experimental tool called “atomic mutagenesis” which allows the site specific incorporation of individual oxidized nucleobases into the ribosome. In the course of this project we will replace all inner shell active site residues by their respective oxidized nucleobase versions. By the planned experiments we will be able to gain molecular insight into the functional consequences of oxidative stress in the catalytic heart ribosome and how this might relate to disease.Accumulating recent evidence identified the ribosome as binding target for numerous small non-protein-coding RNAs (ncRNAs) in various organisms of all three domains of life. Therefore it appears that ribosome-associated ncRNAs (rancRNAs) are a prevalent, yet poorly understood class of cellular transcripts. Here we aim at elucidating the functional mechanisms how stress-induced rancRNAs are capable of fine tuning the rate of protein synthesis in a eukaryal and an archaeal model organism. A comprehensive set of in vivo and in vitro approaches will be employed to characterize the regulatory potential of various rancRNAs during a variety of cellular stress situations.Cumulatively, the proposed research will likely expand our current knowledge of how cells, and in particular how the ribosome, adapt to stress. Specifically this project will reveal the so far elusive RNA biology of the emerging class of rancRNAs during translation control.
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