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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.
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 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.
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)
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)
piRNA processing by a trimeric Schlafen-domain nuclease.
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
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.
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
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.
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.
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.
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.
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.
Falk, Sebastian; Weir, John R; Hentschel, Jendrik; Reichelt, Peter; Bonneau, Fabien; Conti, Elena
Project title: “Characterization of piRNA processing factors in C. elegans" (I 6110)
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)