Translational control by a molecular Trojan Horse

Summary

The tRNA-like structures (TLSs) of prokaryotic transfer-messenger-RNA (tmRNA) and eukaryotic viral RNA such as turnip yellow mosaic virus RNA (RNATYMV) use molecular mimicry to trigger resumption or initiation of protein synthesis in vital regulatory processes. This proposal focuses on the central theme: what are the signals for these TLSs to come into action?
In bacteria, tmRNA functions in a quality-control mechanism and rescues ribosomes that have become stalled during translation. In the filamentous streptomycetes, development and antibiotic production are controlled by Leu-tRNAbldA, decoding the rare UUA codon that occurs almost exclusively in developmental genes. This amazing and unique usage of a specific codon for translational control forms an ideal system to investigate what exactly triggers tmRNA-mediated rescue of ribosomes stalled on rare codons. Is it the unoccupied ribosomal A site, or does it also occur with a filled A site due to a yet unidentified time-clock signal? This is a challenging issue in the tmRNA research field.
As just discovered (Barends et al. (2003) Cell 112, 123-9), RNATYMV is an exciting mega-tmRNA-like molecule, with a valylated TLS as a bait for the entrapment of host ribosomes followed by a forced start of viral polyprotein synthesis. I want to investigate the recognition features of this interaction and whether a similar interaction is also used by other virus families, which may lead to a further break-through in the understanding of viral infection mechanisms.
Apparently, the TLSs in two widely different contexts, RNATYMV and tmRNA, both have remarkable properties in initiation or resumption of ribosomal translation, respectively. In evolutionary terms, both RNA molecules may well have a common ancestry, as molecular fossils from a primitive RNA world. During my proposed research, I will be open-eyed for further serendipitous observations hinting at such an ancient linkage.

Keywords: tRNA-like structure, translation initiation, streptomyces development, plus-strand RNA virus, trans-translation

Output

Scientific article

  • G. Eriani, F. Martin, S. Jaeger, R. Giegé, S. Barends(2005): Expression of metazoan replication-dependent histone genes Biochimie pp. 827 - 834
  • C.W.A. Pleij, A.P. Gultyaev, H.J. Vetten, D.-E. Lesemann, R. Koenig, S. Barends, S. Loss(2005): Nemesia ring necrosis virus: a new tymovirus with a genomic RNA having a histidylatable tobamovirus-like 3' end Journal of General Virology pp. 1827 - 1833 ISSN: 1465-2099.
  • J. Reedijk, C Massera, S. Barends, H Casellas, SJ Teat, M.H. Lutz, G.P. van Wezel, P. Gamez, P.U. Maheswari, S Özalp-Yaman, A.L. Spek, P de Hoog(2007): Unique Ligand-Based Oxidative DNA Cleavage by Zinc(II) Complexes of Hpyramol and Hpyrimol Chemistry - A European Journal

Details

Project number

700.53.402

Main applicant

Dr. S. Barends

Affiliated with

Du Pont

Team members

Dr. S. Barends

Duration

17/05/2004 to 20/08/2007