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The role of specialized ribosomes in stress resistance and healthy aging

English title The role of specialized ribosomes in stress resistance and healthy aging
Applicant Polacek Norbert
Number 162559
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 01.02.2016 - 31.01.2019
Approved amount 211'016.00
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Keywords (5)

cellular aging; translation regulation; posttranscriptional modifications; ribosome structure; regulatory ncRNA

Lay Summary (German)

Lead
Das Altern ist ein komplexer biologischer Prozess der vor allem durch den Verlust des zellulären Gleichgewichts sowie der Anhäufung von Schäden in wichtigen Zellkomponenten gekennzeichnet ist. In den letzten Jahren stellte sich heraus, dass eine Verlangsamung der allgemeinen Proteinsynthese zur deutlichen Verlängerung der Lebensspanne in verschiedenen Modelorganismen führte.
Lay summary

Inhalt und Ziel des Forschungsprojektes

Ziel dieses Forschungsprojektes ist es den molekularen Mechanismen der Zellalterung auf die Spur zu kommen. Im Speziellen werden wir uns der Funktion des Ribosoms während des Alterns in verschiedenen Zellsystemen widmen. Das Ribosom ist ein zentrales Enzym der Zelle, welches für die Proteinsynthese zuständig ist. Über Jahrzehnte hinweg wurde das Ribosom als starre zelluläre Maschine betrachtet. In letzter Zeit stellte sich aber heraus, dass das Ribosom ein dynamisches Partikel ist, das sowohl in seiner Zusammensetzung als auch in seinem Modifikationsmuster variieren kann. Die Rolle solcher „spezialisierter Ribosomen“ in Bezug auf die Zellalterung steht im Mittelpunkt dieses Forschungsvorhabens.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Dieses Projekt ist der Grundlagenforschung zuzuordnen. Im Rahmen des Forschungsvorhabens wollen wir die molekularen Mechanismen der Zellalterung und des Alterns ganzer Organismen verstehen. Das Altern und die damit zusammenhängenden pathologischen Beschwerden rücken immer mehr ins Zentrum von gesundheitspolitischen Überlegungen, vor allem in der westlichen Welt. Nur wenn die molekularen Ursachen für Alters-bedingte Erkrankungen bekannt sind, kann auch zielgerichtet darauf reagiert werden.

Direct link to Lay Summary Last update: 01.02.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Alterations of the translation apparatus during aging and stress response
Gonskikh Yulia, Polacek Norbert (2017), Alterations of the translation apparatus during aging and stress response, in Mechanisms of Ageing and Development, 168, 30-36.

Collaboration

Group / person Country
Types of collaboration
Johannes Grillari Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Martin Kos Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
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
Swiss RNA workshop 2019 Talk given at a conference Modulation of mammalian translation by the tRNA-Pro half 25.01.2019 Bern, Switzerland Gonskikh Yulia;
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 Polacek Norbert;
27th tRNA conference Talk given at a conference The multifaceted roles of ribosome-associated tRNA fragments during translation control 23.09.2018 Strasbourg, France Polacek Norbert;
27th tRNA conference Talk given at a conference Effects of the tRNAPro half on translation in mammalian cells 23.09.2018 Strasbourg, France Gonskikh Yulia;
26th tRNA conference Talk given at a conference The role of tRNA-derived fragments in stress response 04.09.2016 Jeju, Korean Republic (South Korea) Polacek Norbert; Gonskikh Yulia;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
BioChemie am Samstag Talk 11.11.2017 Bern, Switzerland Polacek Norbert;
Education for chemistry teacher Talk 06.03.2017 Bern, Switzerland Polacek Norbert;


Self-organised

Title Date Place
Nacht der Forschung 16.09.2017 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Other activities Nacht der Forschung German-speaking Switzerland 2017

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)
166527 Stress-mediated effects on ribosome functions and translation control 01.07.2016 Project funding (Div. I-III)

Abstract

Aging is a complex process characterized by a decline in cellular homeostasis and accumulation of damage that can lead to age-related pathologies. Novel factors and pathways are constantly emerging, but only few are evolutionarily conserved and well understood. One of the few mechanisms involved in the regulation of aging of a wide range of organisms is the reduction of overall protein translation converging on the ribosome. The ribosome has been seen for decades as a static machine that translates mRNAs into proteins. However, over the last few years it became clear that the ribosome is a dynamic structure that responds to various stimuli by adapting its structure, molecular composition, post-translational and post-transcriptional modification status and in consequence its function. Such structurally distinct ribosomes are postulated to be “specialized ribosomes” comprising peculiar functional properties and are thus considered to be engaged in translating specific subsets of cellular messages. We have recently reported that lack of a single, conserved C5 methylation of ribosomal RNA by deletion of the methyltransferase NSUN5 extends the lifespan and stress resistance of yeast, worms and flies. We could show that lack of methylation at ribosomal RNA residue C2278 alters ribosomal structure and thus translational fidelity, resulting in a ‘reprogramming’ of the ribosome towards translation of mRNAs involved in cellular stress-response. With the proof-of-principle that already a single modification of rRNA does alter the life span of organisms, it becomes clear that a systematic analysis of global post-transcriptional modification patterns of rRNA, including pseudouridinylations and base- and sugar methylations, is of crucial importance to understand the changes of the ribosome in terms of synthesis, composition, structure and function in the context of aging and oxidative stress. For such an undertaking the combined expertise of labs in the fields of biogerontology, ribosome structure/function analysis, as well as ribosome biogenesis are necessary and have joined forces within this joint DACH proposal in deepening and further developing of our already successful collaboration on NSUN5.
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