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The stressed ribosome: from molecular characterization to cellular consequences

English title The stressed ribosome: from molecular characterization to cellular consequences
Applicant Polacek Norbert
Number 188969
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 Biochemistry
Start/End 01.11.2019 - 31.10.2023
Approved amount 632'000.00
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All Disciplines (2)

Discipline
Biochemistry
Molecular Biology

Keywords (6)

stress response; translation regulation; RNA biology; protein synthesis; ncRNA; ribosome

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, (2) das regulatorische Potenzial von Stress-induzierten nicht-kodierenden RNAs (ncRNAs) zu verstehen, sowie (3) die Rolle von ribosomalen RNA Verlängerungen in der Hefe im Vergleich zu bakteriellen Ribosomen während der Stressanpassung zu verstehen. Regulation der Proteinsynthese ermöglicht es Zellen, schnell und effizient auf geänderte Umweltbedingungen reagieren zu können. Um diese Ziele erreichen zu können kommen biochemische, strukturbiologische, genetische, biophysikalische, sowie 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: 14.10.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
166527 Stress-mediated effects on ribosome functions and translation control 01.07.2016 Project funding (Div. I-III)
182880 NCCR RNA & disease: The role of RNA biology in disease mechanisms (phase II) 01.05.2018 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)
181745 Mapping oxidation of the ribosomal RNA via Mass Spectroscopy 01.07.2018 Doc.Mobility

Abstract

The coordinated regulation of gene expression in response to swiftly changing environmental conditions or to intra- and extracellular signals is key for the formation of metabolic networks in all domains of life. The ribosome is an evolutionarily ancient enzyme that plays a central role in the cell metabolism. As a multifunctional ribonucleoprotein particle composed of two unequal subunits, the ribosome translates the genome’s message into all proteins needed for life. Considerable cellular energy resources are needed for orchestrating mRNA translation and therefore it is not surprising that regulation of protein biosynthesis as response to stress or external stimuli is pivotal for the cellular physiology. In fact, it has been shown that the inadequacy of adapting protein biosynthesis rates in response to challenging cues negatively affects protein homeostasis and can lead to cell death and disease. The aim of this proposal is to conduct experiments that will shed light on how the ribosome and the entire translation machinery reacts to different stress situations on the molecular level as well as at the cellular level. In particular we will address three main questions:(i) How do specific oxidative lesions in the ribosomal RNA affect the ribosome’s performance and bacterial cell physiology?(ii) What is the structure-function relationship of ribosome-associated ncRNAs (rancRNAs) during translation regulation?(iii) What are the roles of eukaryal rRNA expansion segments for tuning protein biosynthesis during challenging growth conditions?We will address these questions on the molecular level (e.g. by placing single oxidized nucleosides in the ribosome, or by removing individual rRNA expansion segments), the structural level (we will investigate the mechanism of rancRNA action by solving the cryo-EM structure), and on the cellular level (e.g. growth phenotypes of bacteria and human cells as a consequence of rRNA oxidation or rancRNA binding, respectively). By combining high-throughput approaches (e.g. RNA-Seq, LC-MS/MS) with dedicated classical and advanced biochemical and molecular biology methods, as well as with cutting edge genetic tools, we anticipate novel insights into translation control in bacteria, yeast and human cells. Cumulatively, the research plan will likely deepen our current understanding of how cells, and in particular how the ribosome, adjust to challenging environmental stimuli.
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