Group Sebastian Falk

Biogenesis & Action of small RNAs

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The Question

All cells of an organism contain the same genome. However, the pattern of gene expression differs considerably between different cell types and also changes over time during development. One way to regulate the expression of genes is achieved by small RNAs that together with Argonaute proteins lead to gene silencing in a process called RNA interference (RNAi). In order to generate a robust RNAi response, the small RNAs must be present in sufficient quantities. How is it decided from which endogenous RNA transcripts small RNAs are produced and how are specific small RNAs then selected for amplification process? In the nuclear RNAi pathway small RNA – Argonaute complexes induce histone methylation and thereby heterochromatin formation. How are the Histone methyltransferases recruited and what are the factors involved in the process? Our research will provide fundamental knowledge of the mechanism of gene silencing and in general on the regulation of gene expression.

The Approach

Our group uses an integrated structural biology approach, with structural biological techniques forming the core (X-ray crystallography & single-particle electron microscopy) and complemented by biochemical and biophysical approaches. Our research focuses on the mechanistic characterization of protein complexes, which we obtain by two complementary methods. In the bottom-up approach, we produce and purify individual components or protein subcomplexes, which then can be used for the gradual build-up of increasingly larger assemblies. In the top-down approach, a single subunit of a protein complex carries an affinity tag, which allows purifying stable complexes from endogenous sources that can be utilized for structural studies, but for example also for the identification of new interaction partners by mass spectrometry. To complement our biochemical and structural analysis, we perform in vivo experiments together with our collaboration partners.

Sebastian Falk

Sebastian studied Biochemistry at the University of Bayreuth. He received his Ph.D. from Heidelberg University, where he worked on targeting of membrane proteins with Irmi Sinning. During his postdoc with Elena Conti at the MPI of Biochemistry, he combined structural biology and biochemistry to study eukaryotic RNA degradation. From March 2019 he is a group leader at the Max Perutz Labs in Vienna.

www.falklaboratory.org

Campus Vienna Biocenter 5
1030 Vienna
Room: 1.620

+43-1-4277-74360

Spotlights

PETISCO - piRNA biogensis in C. elegans.

PETISCO is essential for piRNA biogenesis in C. elegans. We have determined the structure of several PETISCO submodules that allow us to propose a model for the PETISCO core complex and how it recognizes the piRNA precursor. (Genes & Development 2021)

The helicase MTR4 is a central platform for binding RNA adapter proteins.

MTR4 is the central cofactor of the RNA Exosome in the nucleus. In addition to providing helicase activity, MTR4 also acts as a central platform for the recruitment of various RNA-binding proteins like NOP53, AIR2, NVL or NRDE2. They all bind to the KOW domain of MTR4 in a mutually exclusive manner using a conserved motif. (Nature Communications 2019)

5′ Processing of piRNAs in C. elegans by PUCH

Together with the Ketting Lab (IMB Mainz) we have discovered the mysterious enzyme complex, PUCH, which processes the 5' end of piRNA precursors in C. elegans.
PUCH consists of three Schlafen-like domains, which are usually found in endoribonucleases that restrict viral replication. Moreover, PUCH locates to the outer mitochondrial surface, similar to Zucchini in flies and mice. (Nature 2023)

Group picture 2019

Celebrating one year of the Falk Lab.

Team

Martin Brehm
PhD Student
+43-1-4277-74361
Room: 1.624

Virginia Busetto
PostDoc
+43-1-4277-74320
Room: 1.624

Sebastian Falk
Group Leader
+43-1-4277-74360
Room: 1.620

Andrej Knarr
Diploma/Master Student
+43-1-4277-61656
Room: 1.624

Kevin Alexander Kranz
Diploma/Master Student
+43-1-4277-74361
Room: 1.624

Raffael Lichtenberger
Lab Manager
+43-1-4277-61656
Room: 1.624

Philipp Mairinger
Diploma/Master Student
+43-1-4277-61656
Room: 1.624

Toni Manolova
PhD Student
+43-1-4277-61656
Room: 1.624

Aswini Kumar Panda
PhD Student
+43-1-4277-52275
Room: 1.321

Selected Publications

piRNA processing by a trimeric Schlafen-domain nuclease.

2023 NATURE;622(7982):402-409.
PMID: 37758951

Podvalnaya, Nadezda; Bronkhorst, Alfred W; Lichtenberger, Raffael; Hellmann, Svenja; Nischwitz, Emily; Falk, Torben; Karaulanov, Emil; Butter, Falk; Falk, Sebastian; Ketting, René F

Structural basis of PETISCO complex assembly during piRNA biogenesis in C. elegans

2021 GENE DEV;35(17-18):1304-1323.
PMID: 34413138

Perez-Borrajero, Cecilia; Podvalnaya, Nadezda; Holleis, Kay; Lichtenberger, Raffael; Karaulanov, Emil; Simon, Bernd; Basquin, Jérôme; Hennig, Janosch; Ketting, René F; Falk, Sebastian

A ribonuclease III involved in virulence of Mucorales fungi has evolved to cut exclusively single-stranded RNA.

2021 NUCLEIC ACIDS RES
PMID: 33877360

Cánovas-Márquez, José Tomás; Falk, Sebastian; Nicolás, Francisco E; Padmanabhan, Subramanian; Zapata-Pérez, Rubén; Sánchez-Ferrer, Álvaro; Navarro, Eusebio; Garre, Victoriano

The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs

2019 NAT COMMUN
PMID: 31358741

Lingaraju, Mahesh; Johnsen, Dennis; Schlundt, Andreas; Langer, Lukas M.; Basquin, Jérôme; Sattler, Michael; Jensen, Torben Heick; Falk, Sebastian; Conti, Elena

Structure of the nuclear exosome captured on a maturing preribosome.

2018 SCIENCE;360(6385):219-222.
PMID: 29519915

Schuller, Jan Michael; Falk, Sebastian; Fromm, Lisa; Hurt, Ed; Conti, Elena

Mpp6 Incorporation in the Nuclear Exosome Contributes to RNA Channeling through the Mtr4 Helicase.

2017 Cell Rep;20(10):2279-2286.
PMID: 28877463

Falk, Sebastian; Bonneau, Fabien; Ebert, Judith; Kögel, Alexander; Conti, Elena

Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53.

2017 RNA;23(12):1780-1787.
PMID: 28883156

Falk, Sebastian; Tants, Jan-Niklas; Basquin, Jerôme; Thoms, Matthias; Hurt, Ed; Sattler, Michael; Conti, Elena

Structure of the RBM7-ZCCHC8 core of the NEXT complex reveals connections to splicing factors.

2016 NAT COMMUN;7:13573.
PMID: 27905398

Falk, Sebastian; Finogenova, Ksenia; Melko, Mireille; Benda, Christian; Lykke-Andersen, Søren; Jensen, Torben Heick; Conti, Elena

The molecular architecture of the TRAMP complex reveals the organization and interplay of its two catalytic activities.

2014 MOL CELL;55(6):856-867.
PMID: 25175027

Falk, Sebastian; Weir, John R; Hentschel, Jendrik; Reichelt, Peter; Bonneau, Fabien; Conti, Elena

Collaborations & Funding

National Scientific Research Fund (FWF) Project

Project title: “Characterization of piRNA processing factors in C. elegans" (I 6110)

Doctoral Program "RNA@core - Molecular mechanisms in RNA biology" (FWF)

doc.funds "RNA@core - Molecular mechanisms in RNA biology" (DOC177)

Coordinator Javier Martinez (Medical Univeristy of Vienna) and Deputy Coordinator: Sebastian Falk (University of Vienna)

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Cell Competition and Tissue Fitness in Development and Disease

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