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Regulation of mRNA translation and its relationship with disease processes

English title Regulation of mRNA translation and its relationship with disease processes
Applicant Zavolan Mihaela
Number 170216
Funding scheme Project funding
Research institution Abteilung Strukturbiologie und Biophysik Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.10.2016 - 31.12.2019
Approved amount 474'000.00
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Keywords (4)

pre-mRNA 3' end processing; mRNA translation; 3'UTR length; cleavage factor I

Lay Summary (German)

Lead
Proteine sind molekulare Maschinen im Mittelpunkt des Lebens in der Zelle. Die exakte Steuerung, welche Proteine in welcher Menge an welchen Ort innerhalb der Zelle produziert werden, spielt eine zentrale Rolle für das richtige Funktionieren der Zelle.
Lay summary

In den vergangenen Jahren sind unzählige Mechanismen entdeckt worden, wie die Bildungsrate von Proteinen und der Ort der Proteinsynthese beeinflusst werden, sei es für Proteine im allgemeinen, oder für einzelne spezielle Proteine. Diese Mechanismen sind äusserst unterschiedlich, angefangen bei zustandsabhängigen Veränderungen in der Verfügbarkeit von transferRNAs (welche die genetische Information in Aminosäureketten „übersetzen“), über Veränderungen in der Verarbeitung von messengerRNA (mRNA, die die genetische Information vom Kern in das Zytoplasma bringen) - Vorlagen durch alternatives Spleissen oder Polyadenylierung, bis hin zu Veränderungen der räumlichen Lage der mRNAs innerhalb der Zelle durch Interaktionen mit verschiedenen RNA-bindenden Proteinen.

 Das Ziel des vorgeschlagenen Projektes ist es zu beschreiben, wie einzelne Mechanismen zur Regulierung der Vorläufer-mRNA-Verarbeitung durch alternative Polyadenylierung (die wir im Rahmen unseres letzten Projektes entdeckt haben) die Proteinsynthese der entsprechenden mRNAs beeinflussen. Da alternative Polyadenylierung im Zusammenhang mit Krebs beobachtet wurde, möchten wir die Regulatoren der Polyadenylierung in Krebszellen identifizieren, ebenso wie die betroffenen mRNAs, und die Art, wie sie die Eigenschaften der Krebszellen beeinflussen.

Obwohl das menschliche Genom nur ungefähr 30‘000 Gene enthält die Proteine kodieren, werden noch viel mehr Proteine und dadurch auch Funktionen durch alternative Verarbeitungsmethoden der Vorläufer-mRNAs (pre-mRNA) erhalten. Mit einem differenzierten Verständnis wie die Produktion der Proteinformen unter unterschiedlichen Bedingungen reguliert wird, hoffen wir neue Wegen zu eröffnen, um das Verhalten von Zellen zu manipulieren und um gezielte Veränderungen des Translationsprozessen für therapeutische Anwendungen zu ermöglichen.

Direct link to Lay Summary Last update: 30.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
PolyASite 2.0: a consolidated atlas of polyadenylation sites from 3′ end sequencing
Herrmann Christina J, Schmidt Ralf, Kanitz Alexander, Artimo Panu, Gruber Andreas J, Zavolan Mihaela (2019), PolyASite 2.0: a consolidated atlas of polyadenylation sites from 3′ end sequencing, in Nucleic Acids Research, 48(D1), D174-D179.
Discovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC
Gruber Andreas J., Schmidt Ralf, Ghosh Souvik, Martin Georges, Gruber Andreas R., van Nimwegen Erik, Zavolan Mihaela (2018), Discovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC, in Genome Biology, 19(1), 44-44.
Terminal exon characterization with TECtool reveals an abundance of cell-specific isoforms
Gruber Andreas J., Gypas Foivos, Riba Andrea, Schmidt Ralf, Zavolan Mihaela (2018), Terminal exon characterization with TECtool reveals an abundance of cell-specific isoforms, in Nature Methods, 15(10), 832-836.
3' End Sequencing Library Preparation with A-seq2
Martin Georges, Schmidt Ralf, Gruber Andreas J., Ghosh Souvik, Keller Walter, Zavolan Mihaela (2017), 3' End Sequencing Library Preparation with A-seq2, in Journal of Visualized Experiments, (128), 56129.

Collaboration

Group / person Country
Types of collaboration
Maria Carmo-Fonseca Portugal (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Lukas Jeker, Department of Biomedicine, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Arnaud Scherberich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
André Gerber Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Bioinformatics and Genomics Workshop Talk given at a conference The role of 3’ end processing in defining mammalian cell types 17.12.2019 Barcelona, Spain Zavolan Mihaela;
EMBO workshop ‘RNP network dynamics in development and disease’ Talk given at a conference The RNP code of 3’ end processing 29.09.2019 Ljubljana, Slovenia Zavolan Mihaela;
Seminar series CRG Individual talk Regulation of 3’ end processing in relation to cellular fate 24.06.2019 Lausanne, Switzerland Zavolan Mihaela;
EMBO workshop Regulatory epigenomics: from large data to useful models Talk given at a conference Regulation of 3’ end processing in relation to cellular fate 10.03.2019 Chennai, India Zavolan Mihaela;
Microsymposium Talk given at a conference Cell-type-specific 3' end processing expands the functional repertoire of mammalian mRNAs 18.06.2018 Vienna, Austria Zavolan Mihaela;
Stop Cancer Talk given at a conference Transcriptome analyses of human cancers 13.04.2018 Bucharest, Romania Zavolan Mihaela;
Seminar series Helmholtz Zentrum Individual talk Cell-type-specific 3' end processing expands the functional repertoire of mammalian mRNAs 15.02.2018 Munich, Germany Zavolan Mihaela;
Computational RNA Biology Conference Poster A comprehensive analysis of 3’ end sequencing data sets reveals novel polyadenylation signals and regulators of alternative polyadenylation 29.09.2017 EBI - UK is not available as an option in drop down list, United States of America Gruber Andreas;
Cold Spring Harbor Laboratory Systems Biology workshop Talk given at a conference Pre-mRNA splicing and polyadenylation in cell type specification 02.03.2017 Cold Spring Harboer, United States of America Zavolan Mihaela;
Systems Biology: Global Regulation of Gene Expression Conference Poster A comprehensive analysis of 3' end sequencing data sets reveals novel polyadenylation signals and the repressive role of HNRNP C on cleavage and polyadenylation 26.02.2017 Cold Spring Harbor, United States of America Gruber Andreas;
Seminar series Individual talk Generation and functional relevance of 3’ end transcript isoforms 24.01.2017 Heidelberg, Germany Zavolan Mihaela;
Biozentrum Symposium Individual talk A comprehensive analysis of 3' end sequencing data sets reveals novel polyadenylation signals and regulators of alternative polyadenylation 14.01.2017 Basel, Switzerland Gruber Andreas;


Awards

Title Year
J.C.W Shepherd prize for scientific excellence 2017
Postdoc mobility fellowship 2017

Associated projects

Number Title Start Funding scheme
189063 Cell type-specific expression of 3’ untranslated region isoforms: quantification, modeling, and prediction of functional impact 01.01.2020 Project funding
147013 Inference of combined quantitative effects of miRNAs and transcription factors on gene expression 01.04.2013 Project funding
160760 Molecular underpinnings of age-related muscle loss 01.01.2016 Sinergia
143977 The molecular biology of RNA 3' end processing 01.10.2012 Project funding

Abstract

Protein synthesis is at the core of cellular life. Consequently, a vast proportion of a cell's resources is dedicated to this process, which is reflected in the ribosomes taking up a large fraction of a cell's mass. Proliferative states are associated with a further increase in the fraction of the cellular mass dedicated to the translation machinery. The translation process is targeted by many antibacterial agents which exploit the fact that bacterial ribosomes differ from those of eukaryotes. Moreover, a global reduction in translation by means of inhibiting the RNA polymerase I is being explored as a therapeutic possibility in cancers. In recent years, novel mechanisms for modulating the rate, efficiency or site of translation, either globally or for specific transcripts, in relation to the cellular state have been uncovered. Among these are condition-specific alterations in transfer RNA abundance, expression of particular ribosomal proteins in specific disease states, the change in the RNA-binding protein interactome of transcripts through alternative polyadenylation, and RNA modifications such as the 1 or 6-methyladenosine. Nevertheless, the relative importance of translation and transcription regulation for gene expression is highly debated and the breadth and mechanisms underlying dynamic changes in translation are not well understood. Evidence has started to emerge that dynamic sub-cellular structures that are organized in part by multi-valent RNAs and in part by proteins with intrinsically disordered domains play a role. The aim of the project proposed here is to characterize the role of specific mechanisms that we have uncovered in our previous work, in modulating mRNA translation in relation to normal and disease states. Thus, we would like to investigate the impact on mRNA translation of systematic changes in 3’UTR lengths as a result of changes in cell state (e.g. cell differentiation) or in the expression of regulators of 3’UTR length. Having already identified systems in which the aforementioned behaviors can be studied, we would now like to undertake their molecular characterization and evaluate their relevance for cell differentiation, development and cancer. Succinctly, the work outlined in this proposal aims to elucidate cell type-specific translational programs that are rooted in specific regulators and could open new avenues for engineering cellular behaviors. At the same time, we hope that through a nuanced understanding of how translation is regulated in different conditions we will enable targeted manipulations of the process for therapeutic applications.
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