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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.
VBC5
Room: 1.620
+43 1 4277 74360
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)
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)
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
Maximillian Mager
PhD 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
MUT-7 exoribonuclease activity and localization are mediated by an ancient domain.
Busetto Virginia, Pshanichnaya Lizaveta, Lichtenberger Raffael, Hann Stephan, Ketting René F, Falk Sebastian
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 .
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, Heick Jensen Torben, 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)