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How is protein synthesis controlled by regulatory factors?

How is protein synthesis controlled by regulatory factors?. miRNAs and RNA-binding proteins - trans-regulators of protein synthesis. 1990-ies: RNA-binding proteins control protein synthesis at distinct steps. “Fail-safe” control of 43S recruitment and scanning. Steric regulation of 43S

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How is protein synthesis controlled by regulatory factors?

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  1. How is protein synthesis controlled by regulatory factors?

  2. miRNAs and RNA-binding proteins - trans-regulators of protein synthesis

  3. 1990-ies: RNA-binding proteins control protein synthesis at distinct steps “Fail-safe” control of 43S recruitment and scanning Steric regulation of 43S complex recruitment Regulation of 60S ribosomal subunit joining Ostareck et al., Cell (2001) Beckmann et al., Cell (2005) Muckenthaler et al., Molecular Cell (1998)

  4. Regulation of msl-2 translation by SXL Duncan et al., Genes Dev 2006 Abaza et al., Genes Dev 2006 Beckmann et al., Cell 2005

  5. UAA UAA uORFs: common elements that affect translation 7mG AUG AAAAAA AUG

  6. A system for translational control of msl-2 mRNA by SXL in vitro X X

  7. A uAUG is critical for translational regulation of msl-2 mRNA by SXL Luciferase assay

  8. The uORF is conserved among Drosophilids

  9. What is the function of the uORF? Is uORF translation required for its effect on translational control? Or is it the binding site for a co-repressor?

  10. Elongation at the uORF is not required for SXL-mediated translational repression Binding of a co-repressor is very unlikely Elongation at uORF is not required for regulation

  11. Upstream translation initiation is important for strong regulation Recognition of the uAUG by the translation machinery is required for regulation

  12. SXL promotes uAUG recognition SXL promotes uAUG recognition

  13. SXL enhances uORF-mediated repression of downstream translation

  14. GST-Pulldown Yeast-Two-Hybrid Assay eIF3i directly interacts with SXL

  15. Summary • A uORF is critical for translational regulation of msl-2 mRNA by SXL via the 5’ UTR • uAUG recognition is important, elongation is not • SXL promotes recognition of the uAUG • SXL enhances the inhibitory effect of the uORF • SXL performs a specific function that cannot be recapitulated by PTB • SXL interacts with eIF3i suggesting that SXL might directly influence eIF3 function A new function for uORFs: exception or ‘tip of the iceberg’?

  16. Model for factor-mediated regulation of uORF function • SXL promotes uORF recognition • SXL enhances uORF-mediated repression of downstream translation • Functional importance of SXL-eIF3i interaction? • A new theme for translational control via uORFs? J. Medenbach, unpublished

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