Translational control of msl-2 mRNA: unravelling a new uORF function

• Applicant: Professor Dr. Matthias Hentze
• Subject Area: Cell Biology
• Term: from 2007 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33442413

Translational repression of msl-2 mRNA mediated by binding of sex lethal (SXL) to sites in both the 5’ and 3’ UTR is important in female flies for dosage compensation and survival. Previously, we estab-lished a Drosophila embryo in vitro system that faithfully recapitulates this translational response. We showed that SXL interferes with ribosomal scanning via the 5’ UTR binding site, while association of SXL and the corepressor protein UNR with the 3’ UTR inhibits 43S recruitment. During the current funding cycle we demonstrated that 3’UTR control involves the poly(A)-tail and PABP. Since ‘closed-loop’ formation still occurs on the repressed mRNA, we identified a novel mechanism of translational control. We now propose to focus on the mechanism of 5’UTR-mediated regulation of ribosomal scanning by SXL. Preliminary data have shown that this mechanism requires an upstream open reading frame (uORF), and that SXL augments the repressive effect of the uORF by an unknown mechanism. We will dissect this new paradigm of RNA-binding protein-regulated uORF function mechanistically, and explore the scope of this mechanism in the regulation of the transcriptome.

• DFG Programme: Research Units
• Subproject of: FOR 855: Cytoplasmic Regulation of Gene Expression