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Mechanisms and Developmental Functions of MicroRNA Turnover: The Exoribonuclease XRN2

English title Mechanisms and Developmental Functions of MicroRNA Turnover: The Exoribonuclease XRN2
Applicant Grosshans Helge
Number 143313
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.02.2013 - 30.09.2016
Approved amount 690'000.00
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Keywords (10)

miRNA turnover; MicroRNA (miRNA); C. elegans; noncoding RNA; XRN2; posttranscriptional gene regulation; genetics; genomics; biochemistry ; development

Lay Summary (German)

Lead
MikroRNAs (miRNAs) sind eine neue Klasse regulatorischer RNAs. Sie binden mRNAs, um diese abzuschalten. Jede der mehreren hundert unterschiedlichen miRNAs reguliert etliche Ziel-mRNAs, so dass sie für die Genregulation bedeutsam sind und diverse zelluläre und Entwicklungsprozesse beeinflussen. MikroRNAs sind daher selbst ebenfalls stark reguliert, und umgekehrt trägt die Deregulierung von miRNAs zu Krankheiten wie Krebs bei. Die relevanten Mechanismen sind nur ansatzweise verstanden.
Lay summary

Inhalt und Ziel des Forschungsprojektes

Wir haben kürzlich im Fadenwurm Caenorhabditis elegans gezeigt, dass Ribonukleasen (RNasen) die Aktivität von miRNAs durch ihren Abbau hemmen. Insbesondere haben wir die RNase XRN2 als wichtigen Faktor in diesem Prozess identifiziert. In anderen Organismen (Mensch, Hefe) spielt XRN2 darüberhinaus ein wichtige Rolle in der Herstellung oder dem Abbau verschiedener anderen RNAs. Unser Ziel ist daher, im Detail zu verstehen, wie XRN2 funktioniert. Ein besonderer Fokus liegt auf der Identifizierung seiner möglichen Kofaktoren und/oder Regulatoren, insbesondere solcher Faktoren, die für die Degradation von miRNAs bedeutsam sind. Weiterhin zielen wir darauf, unser Verständnis für die Bedeutung des miRNA-Abbaus in der Entwicklung des Fadenwurms zu vertiefen. Zu diesem Zweck wenden wir eine Kombination von genetischen, biochemischen, genomischen und zellbiologischen Methoden an.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit wird neue Einsichten in die Komplexität und Dynamik der miRNA-vermittelten Gensteuerung generieren und damit unser Verständnis der Regulationsmechanismen der Genexpression vertiefen. Dieses Wissen ist eine notwendige Grundlage für zukünftige Forschung zur gezielten Modulation der Genexpression zu therapeutischen Zwecken.

Keywords

MicroRNA (miRNA), noncoding RNA, RNA turnover, post-transcriptional gene regulation, C. elegans, XRN2, genomics, genetics, biochemistry, cell biology, development

Direct link to Lay Summary Last update: 19.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Two distinct transcription termination modes dictated by promoters
Miki Takashi S., Carl Sarah H., Großhans Helge (2017), Two distinct transcription termination modes dictated by promoters, in Genes & Development, 31(18), 1870-1879.
Structural basis and function of XRN2 binding by XTB domains.
Richter Hannes, Katic Iskra, Gut Heinz, Großhans Helge (2016), Structural basis and function of XRN2 binding by XTB domains., in Nature structural & molecular biology, 23(2), 164-71.
XRN2 Autoregulation and Control of Polycistronic Gene Expression in Caenorhabditis elegans
Miki Takashi S., Carl Sarah H., Stadler Michael B., Großhans Helge (2016), XRN2 Autoregulation and Control of Polycistronic Gene Expression in Caenorhabditis elegans, in PLOS Genetics, 12(9), e1006313-e1006313.
The ribonucleotidyl transferase USIP-1 acts with SART3 to promote U6 snRNA recycling.
Rüegger Stefan, Miki Takashi S, Hess Daniel, Großhans Helge (2015), The ribonucleotidyl transferase USIP-1 acts with SART3 to promote U6 snRNA recycling., in Nucleic Acids Research, 43, 3344-3357.
Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover
Miki Takashi S., Rueegger Stefan, Gaidatzis Dimos, Stadler Michael B., Grosshans Helge (2014), Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover, in NUCLEIC ACIDS RESEARCH, 42(6), 4056-4067.
PAXT-1 Promotes XRN2 Activity by Stabilizing It through a Conserved Domain
Miki Takashi S., Richter Hannes, Rueegger Stefan, Grosshans Helge (2014), PAXT-1 Promotes XRN2 Activity by Stabilizing It through a Conserved Domain, in MOLECULAR CELL, 53(2), 351-360.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EpiGeneSwiss Meeting Talk given at a conference Widespread read-through identifies a role for XRN2 in transcription termination in C.elegans 06.06.2016 Weggis, Switzerland Carl Sarah;
1st NCCR RNA & Disease retreat Talk given at a conference Regulation of gene expression by the RNase XRN2 19.01.2016 Kandersteg, Switzerland Takashi Miki;
TERM14 (Tiny European RNA Meeting #14) Talk given at a conference The Silence of RNA: Mechanisms and Functions 14.12.2015 Paris, France Grosshans Helge;
MicroRNAs and Noncoding RNAs in Cancer Talk given at a conference The Yin and Yang of miRNAs and Their Targets 07.06.2015 Keystone, CO, United States of America Grosshans Helge;
10th Microsymposium on Small RNAs Talk given at a conference Targets and Regulation of MicroRNAs 04.05.2015 Vienna, Austria Grosshans Helge;
IRI-LS Symposium: From RNA Pools to Single RNA Molecules Talk given at a conference Functional insights into RNA metabolism and the dynamic transcriptome 25.03.2015 Berlin, Germany Grosshans Helge;
Swiss RNA Workshop Poster Potent degradation of neuronal miRNAs induced by highly complementary targets 23.01.2015 Berne, Switzerland De la Mata Manuel;
C. elegans Development, Cell Biology and Gene Expression Meeting in association with The 6th Asia-Pacific C. elegans Meeting Talk given at a conference Essential roles of XRN2 and its novel binding partner PAXT-1 in RNA turnover and C. elegans development 15.07.2014 Nara, Japan Takashi Miki;
Workshop "20 years of microRNA research, current challenges and the way onward" Talk given at a conference Towards a (more) quantitative understanding of miRNAs in physiology 24.01.2014 McGill University's Bellairs Research Station, Holetown, Barbados Grosshans Helge;
Yale University Dept. Genetics Seminar Individual talk Timing C. elegans development with transcriptional oscillations and miRNAs 23.01.2014 New Haven, CT, United States of America Grosshans Helge;
RNA 2013 The 18th annual meeting of the RNA Society Talk given at a conference PAXT-1 binds XRN-2 and promotes its activity 11.06.2013 Davos, Switzerland Takashi Miki;
EMBO Conference Eukaryotic RNA Turnover: From Structural Insights to Diseases Talk given at a conference PAXT-1 binds XRN-2 and promotes its activity 21.04.2013 Strasbourg, France Takashi Miki;
Basel Worm Meeting Talk given at a conference PAXT-1 binds XRN-2 and promotes its activity 14.03.2013 Basel, Switzerland Takashi Miki;


Associated projects

Number Title Start Funding scheme
163447 Post-transcriptional gene regulation in development: the function of LIN-41/TRIM71 01.06.2016 Project funding (Div. I-III)
127052 Mechanisms of microRNA biogenesis and turnover 01.02.2010 Project funding (Div. I-III)

Abstract

MicroRNAs (miRNAs) are a novel class of gene regulators that make up >1% of genes in a typical animal genome. Through an antisense mechanism, they control a large number of target mRNAs, thus constituting an important layer of gene regulation that affects diverse cellular and developmental processes. Accordingly, miRNA levels are highly regulated, although the relevant mechanisms are generally not well understood. Conversely, miRNA dysregulation has been implicated in many diseases, most notably diverse cancers. Our objective is to understand how and to what end degradation of mature miRNAs modulates miRNA activity. Using the nematode Caenorhabditis elegans, we have recently shown that this process is important for miRNA homeostasis, and, at least in part, controlled by the exoribonuclease XRN2. We propose to dissect in more detail how XRN2 functions in miRNA turnover, what its cofactors are, and what the relevance of miRNA turnover is for development. XRN2 in other organisms is involved in processing or degrading other RNA substrates, and we expect to gain additional insights into those processes as well. To achieve our goals, we will apply a combination of molecular biology, genetics, biochemistry, genomics, and cell biology. We expect that our studies will generate insights into the increasing complexity and dynamic of post-transcriptional gene regulation.
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