Deutsch
    DFG Research Group FOR855

    Functional characterization of factors implicated in the translational control of TOP-mRNAs

    Prof. Dr. Utz Fischer

    Project Summary:

    Several proteins of the translation apparatus (e.g. ribosomal proteins and elongation factors) are themselves subject to regulation at the level of translation. The mRNAs encoding for these proteins contain a unique sequence motif at their 5’-ends, termed the 5’ Terminal OligoPyrimidine tract, or TOP motif. This motif constitutes the core cis-regulatory element of all these messages. As a response to insufficient nutrition of a cell, TOP mRNAs are deposited in messenger ribonucleoprotein particles (mRNPs) of unknown composition and thereby prevented from translation. Despite intense efforts to unravel functional details of this regulatory event, neither its underlying mechanism nor the trans-acting factors that bind to the TOP motif are known to date. Using an affinity purification strategy, we have recently identified factors that specifically interact with TOP-mRNAs and affect their translation in vitro. The aim of this project is to characterize these candidate proteins and elucidate their function in the regulation of TOP-mRNAs.

    Selected publications (2007-09):

    1.    Petri, S., Grimmler, M., Over, S., Fischer, U., and Gruss, O. 2007. Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cg governs Cajal body localization and stability of the SMN-complex. J. Cell Biol., 179:451-465

    2.    Markert, A., Grimm, M., Martinez, J., Wiesner, J., Meyerhans, A., Meyuhas, O., Sickmann, A. and Fischer, U. 2008. The La-related protein, Larp7, is a component of the 7SK snRNP and affects Tat-dependent transcription of HIV-1. EMBOrep. 9:569-575

    3.    Günther, UP., Handoko, L., Laggerbauer, B., Chari, A., Sickmann, A., Gehring, N., Sendtner, M., Hübner, C., Schülke, M., von Au, K., and Fischer, U. 2009. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1. Human Molecular Genetics, Vol. 18, No. 7 1288–1300.

    4.    Kroiss, M., Schultz, J., Wiesner, J., Chari, A., Sickmann, A., and Fischer, U. 2008. Evolution of an RNP assembly system: a minimal SMN-complex facilitates formation of U snRNPs in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA, 105:10045-10050

    5.    Linder, B., Plöttner O., Kroiss, M., Hartmann, E., Laggerbauer, B, Meister, G. and Fischer, U. 2008. TDRD3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP. Hum.Mol.Genet. 17:3236-46.

    6.    Chari, A., Golas, M., Neuenkirchen, N., Klingenhäger, M., Sander, B., Englbrecht, C., Sickmann, A., Stark, H. and Fischer, U. 2008. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell, 135:497-509.

    7.    Scheller, N., Mina, L.B., Galão, R.P., Chari, A., Giménez-Barcons, M., Noueiry, A., Fischer, U., Meyerhans, A. and Diez, J. 2009.. Translation and replication of hepatitis C virus genomic RNA depends on ancient cellular proteins that control mRNA fates. Proc. Natl. Acad. Sci. USA, in press.