Functional analysis of the TTF complex and its role in neurodevelopmental diseases
Molecular Biology and Physiology of Neurons and Glial Cells
Cell Biology
Final Report Abstract
Topoisomerases are enzymes that act predominantly, if not exclusively, on DNA substrates in cells of all kingdoms. It was therefore a surprise when we could show that eukaryotic topoisomerase TOP3ß is a cytosolic RNA binding protein that exhibits enzymatic activity on RNA substrates in vitro. It was further revealed that TOP3ß forms together with TDRD3, a scaffolding protein, and FMRP, affected in Fragile X mental retardation syndrome (FXS) an as yet unknown trimeric complex in vivo. In this project we have elucidated the role of this unit, which we have named TOP3ß-TDRD3-FMRP (TTF)- complex in RNA metabolism by identifying its RNA targets in vivo and determining its catalytic and/or regulatory function in RNA metabolism. We showed that the TTF complex is recruited to mRNPs via the exon junction complex (EJC) in a sequence independent manner. The biochemical composition of TTF-containing mRNPs and their association with polysomes further suggests that they are engaged in the pioneer round of translation. These studies also helped to shed light on a potential RNA-based etiology of neuropsychiatric disorders. In addition, we investigated the cellular functions of the La-related protein Larp4B, as well as the helicase IGHMBP2, linked to the neuromuscular disorder DSMA1. Both proteins were shown to interact with specific sets of cellular mRNA targets and regulate their translational output.
Publications
- „Untersuchung zur Rolle des La-verwandten Proteins LARP4B im mRNA-Metabolismus“
Maritta Küspert
- Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes (2015). EMBO molecular medicine 7 (12), 1565-1579
Stepniak B, Kästner A, Poggi G, Mitjans M, Begemann M, Hartmann A, Van der Auwera S, Sananbenesi F, Krueger-Burg D, Matuszko G, Brosi C, Homuth G, Völzke H, Benseler F, Bagni C, Fischer U, Dityatev A, Grabe HJ, Rujescu D, Fischer A, Ehrenreich H.
(See online at https://doi.org/10.15252/emmm.201505696) - LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation (2015). RNA 21 (7), 1294-1305
M Küspert, Y Murakawa, K Schäffler, JT Vanselow, E Wolf, S Juranek, A. Schlosser, M. Landthaler and U Fischer
(See online at https://doi.org/10.1261/rna.051441.115) - mRNA metabolism and neuronal disease (2015). FEBS Letters 589 (14), 1598-1606
B Linder, U Fischer, NH Gehring
(See online at https://doi.org/10.1016/j.febslet.2015.04.052) - ProteoPlex: stability optimization of macromolecular complexes by sparse-matrix screening of chemical space (2015). Nature Methods 12 (9), 859-865
Chari A, Haselbach D, Kirves JM, Ohmer J, Paknia E, Fischer N, Ganichkin O, Möller V, Frye JJ, Petzold G, Jarvis M, Tietzel M, Grimm C, Peters JM, Schulman BA, Tittmann K, Markl J, Fischer U, Stark H.
(See online at https://doi.org/10.1038/NMETH.3493) - Loss of LARP4B, an early event in the tumorigenesis of brain cancer? (2016). Translational Cancer Research 5 (S6)
S Blagden, C Schneider, U Fischer
(See online at https://doi.org/10.21037/tcr.2016.11.33) - Deciphering the mRNP code: RNA-bound determinants of post-transcriptional gene regulation (2017). TIBS 42 (5), 369-382
NH Gehring, E Wahle, U Fischer
(See online at https://doi.org/10.1016/j.tibs.2017.02.004) - „Functional characterization of the TTF complex and its role in neurodevelopmental disorders “
Cornelia Brosi
(See online at https://dx.doi.org/10.25972/OPUS-15778) - Impaired local translation of β-actin mRNA in Ighmbp2-deficient motoneurons: implications for spinal muscular atrophy with respiratory distress (SMARD1) (2018). Neuroscience 386, 24-40
Surrey V, Zöller C, Lork AA, Moradi M, Balk S, Dombert B, Saal-Bauernschubert L, Briese M, Appenzeller S, Fischer U, Jablonka S.
(See online at https://doi.org/10.1016/j.neuroscience.2018.06.019) - Crystal Structure of a Variant PAM2 Motif of LARP4B Bound to the MLLE Domain of PABPC1 (2020). Biomolecules 10 (6), 872
C Grimm, JP Pelz, C Schneider, K Schäffler, U Fischer
(See online at https://doi.org/10.3390/biom10060872) - The SARS-CoV-2 RNA–protein interactome in infected human cells (2020). Nature Microbiology, 1-15
Schmidt N, Lareau CA, Keshishian H, Ganskih S, Schneider C, Hennig T, Melanson R, Werner S, Wei Y, Zimmer M, Ade J, Kirschner L, Zielinski S, Dölken L, Lander ES, Caliskan N, Fischer U, Vogel J, Carr SA, Bodem J, Munschauer M.
(See online at https://doi.org/10.1038/s41564-020-00846-z)
