SPP 1935: Deciphering the mRNP code: RNA-bound determinants of post-transcriptional gene regulation
Zusammenfassung der Projektergebnisse
How the expression of eukaryotic protein-coding genes is regulated in response to developmental or environmental cues is a central question of molecular life sciences. Intuitively one would expect that the formation of mRNA by transcription is the crucial event in gene expression regulation and indeed many examples have been described in the past. However, discoveries of recent years have also uncovered posttranscriptional mechanisms that have profound effects on gene expression. No matter whether these mechanisms occur cotranscriptionally or post-transcriptionally, they ultimately regulate protein synthesis, either directly, by affecting the rate of translation, or indirectly, by affecting the mRNA. The life of any give mRNA is very complex: Before its translation at the ribosome can occur, several post-transcriptional steps must be completed, including the proper processing of mRNA, correct transport to, and localization within the cytoplasm. In addition, the availability of mRNAs can also be restrained by translational silencing or controlled decay. The fate of mRNA is at all stages of their life tightly connected to trans-acting factors that interact with the mRNA and form so-called mRNA-protein complexes (mRNPs). Because there are many mRNA-interacting factors and each mRNA is the blueprint of a particular gene, the resulting mRNPs are unique in their composition. The basis of this iniative was the assumption that an “mRNP code” exist, i.e. specific sets of proteins (RNA-binding proteins; RBPs), non-coding RNAs and other molecules that control mRNA fate and function in every cell. In this initiative new technologies in combination with classical biochemistry, structural biology, genetics and cell biology were employed to decipher this “mRNP code”. As outlined in more detail in the following sections, members of this constortium identified thus far unkown components of individual mRNPs, analyzed how they are assembled, disassembled and remodeled and how the composition of mRNPs influenced processing, function, localization and decay. Detailed characterization of individual mRNPs lead to the discovery of new principles of gene expression regulation. In addition, insights into the molecular mechanisms of mRNP formation and function helped understanding other RNPs, which, due to their complex architecture, represent the most versatile class of molecular machines in living organisms. Notably, knowledge obtained within this SPP is of utmost medical relevance as mis-regulation of mRNP metabolism is increasingly recognized as a major contributor to major human disorders including neurological diseases and cancer.
Projektbezogene Publikationen (Auswahl)
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Specific RNP capture with antisense LNA/DNA mixmers. RNA, 23(8), 1290-1302.
Rogell, Birgit; Fischer, Bernd; Rettel, Mandy; Krijgsveld, Jeroen; Castello, Alfredo & Hentze, Matthias W.
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Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nature Communications, 9(1).
Rehage, Nina; Davydova, Elena; Conrad, Christine; Behrens, Gesine; Maiser, Andreas; Stehklein, Jenny E.; Brenner, Sven; Klein, Juliane; Jeridi, Aicha; Hoffmann, Anne; Lee, Eunhae; Dianzani, Umberto; Willemsen, Rob; Feederle, Regina; Reiche, Kristin; Hackermüller, Jörg; Leonhardt, Heinrich; Sharma, Sonia; Niessing, Dierk & Heissmeyer, Vigo
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Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3. Nature Communications, 10(1).
Schneider, Tim; Hung, Lee-Hsueh; Aziz, Masood; Wilmen, Anna; Thaum, Stephanie; Wagner, Jacqueline; Janowski, Robert; Müller, Simon; Schreiner, Silke; Friedhoff, Peter; Hüttelmaier, Stefan; Niessing, Dierk; Sattler, Michael; Schlundt, Andreas & Bindereif, Albrecht
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Grad-seq shines light on unrecognized RNA and protein complexes in the model bacterium Escherichia coli. Nucleic Acids Research, 48(16), 9301-9319.
Hör, Jens; Di Giorgio, Silvia; Gerovac, Milan; Venturini, Elisa; Förstner, Konrad U & Vogel, Jörg
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LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice. Molecular Cell, 77(5), 999-1013.e6.
Wang, Xin; Li, Zhi-Tong; Yan, Yue; Lin, Penghui; Tang, Wei; Hasler, Daniele; Meduri, Rajyalakshmi; Li, Ye; Hua, Min-Min; Qi, Hui-Tao; Lin, Di-Hang; Shi, Hui-Juan; Hui, Jingyi; Li, Jinsong; Li, Dangsheng; Yang, Jian-Hua; Lin, Jinzhong; Meister, Gunter; Fischer, Utz & Liu, Mo-Fang
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The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness. Molecular Cell, 77(5), 1014-1031.e13.
Hasler, Daniele; Meduri, Rajyalakshmi; Bąk, Maciej; Lehmann, Gerhard; Heizinger, Leonhard; Wang, Xin; Li, Zhi-Tong; Sement, François M.; Bruckmann, Astrid; Dock-Bregeon, Anne-Catherine; Merkl, Rainer; Kalb, Reinhard; Grauer, Eva; Kunstmann, Erdmute; Zavolan, Mihaela; Liu, Mo-Fang; Fischer, Utz & Meister, Gunter
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The SARS-CoV-2 RNA–protein interactome in infected human cells. Nature Microbiology, 6(3), 339-353.
Schmidt, Nora; Lareau, Caleb A.; Keshishian, Hasmik; Ganskih, Sabina; Schneider, Cornelius; Hennig, Thomas; Melanson, Randy; Werner, Simone; Wei, Yuanjie; Zimmer, Matthias; Ade, Jens; Kirschner, Luisa; Zielinski, Sebastian; Dölken, Lars; Lander, Eric S.; Caliskan, Neva; Fischer, Utz; Vogel, Jörg; Carr, Steven A.; ... & Munschauer, Mathias
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Deep and accurate detection of m6A RNA modifications using miCLIP2 and m6Aboost machine learning. Nucleic Acids Research, 49(16), e92-e92.
Körtel, Nadine; Rücklé, Cornelia; Zhou, You; Busch, Anke; Hoch-Kraft, Peter; Sutandy, F X Reymond; Haase, Jacob; Pradhan, Mihika; Musheev, Michael; Ostareck, Dirk; Ostareck-Lederer, Antje; Dieterich, Christoph; Hüttelmaier, Stefan; Niehrs, Christof; Rausch, Oliver; Dominissini, Dan; König, Julian & Zarnack, Kathi
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Validation and classification of RNA binding proteins identified by mRNA interactome capture. RNA, 27(10), 1173-1185.
Vaishali, NA; Dimitrova-Paternoga, Lyudmila; Haubrich, Kevin; Sun, Mai; Ephrussi, Anne & Hennig, Janosch
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An unusual mode of baseline translation adjusts cellular protein synthesis capacity to metabolic needs. Cell Reports, 41(2), 111467.
Schneider, Cornelius; Erhard, Florian; Binotti, Beyenech; Buchberger, Alexander; Vogel, Jörg & Fischer, Utz
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FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns. Molecular Cell, 83(15), 2653-2672.e15.
Ebersberger, Stefanie; Hipp, Clara; Mulorz, Miriam M.; Buchbender, Andreas; Hubrich, Dalmira; Kang, Hyun-Seo; Martínez-Lumbreras, Santiago; Kristofori, Panajot; Sutandy, F.X. Reymond; Llacsahuanga Allcca, Lidia; Schönfeld, Jonas; Bakisoglu, Cem; Busch, Anke; Hänel, Heike; Tretow, Kerstin; Welzel, Mareen; Di Liddo, Antonella; Möckel, Martin M.; Zarnack, Kathi; ... & König, Julian
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Massively parallel identification of mRNA localization elements in primary cortical neurons. Nature Neuroscience (c(2023, 1, 16)).
Mendonsa, Samantha; von Kügelgen, Nicolai; Dantsuji, Sayaka; Ron, Maya; Breimann, Laura; Baranovskii, Artem; Lödige, Inga; Kirchner, Marieluise; Fischer, Meret; Zerna, Nadja; Bujanic, Lucija; Mertins, Philipp; Ulitsky, Igor & Chekulaeva, Marina
