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mRNA PowerPoint Presentation

mRNA

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mRNA

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  1. mRNA Cap Poly(A) tail Secondary structures IRES uORF Protein/RNA binding sites AUG Kozak consensus sequence: GCC(A/G)CCAUGG Fátima Gebauer & Matthias W. Hentze Nature Reviews Molecular Cell Biology 5, 827-835 (2004)

  2. Scanning model of Cap-dependent Translation Initiation E P A eIF5B Fátima Gebauer & Matthias W. Hentze Nature Reviews Molecular Cell Biology 5, 827-835 (2004) E P A

  3. http://departments.oxy.edu/biology/Stillman/bi221/091300/091300_lecture_figures.htmhttp://departments.oxy.edu/biology/Stillman/bi221/091300/091300_lecture_figures.htm

  4. Scanning model of Cap-dependent Translation Initiation E P A eIF5B Fátima Gebauer & Matthias W. Hentze Nature Reviews Molecular Cell Biology 5, 827-835 (2004) E P A

  5. Translation of mRNAs in ∆eIF5B Yeast { Polysomes { Actin Northern

  6. Global Regulation

  7. Recycling of the ternary complex requires eIF2B Fátima Gebauer & Matthias W. Hentze Nature Reviews Molecular Cell Biology 5, 827-835 (2004)

  8. eIF2 Phosphorylation Reduces Ternary Complex Starvation (GCN2) Viral infection, apoptisis (PKR) ER Stress (PERK) Haemin-regulated inhibitor (HRI) Fátima Gebauer & Matthias W. Hentze Nature Reviews Molecular Cell Biology 5, 827-835 (2004)

  9. uORFS 1 2 3 4 GCN4

  10. uORFs function in Gcn4 translational control

  11. GCN4: Non-starvation Starvation

  12. eIF4E binding proteins: 4E-BP Apoptosis Insulin AA (Leucine) Cell Proliferation

  13. SJ Morley, MJ Codwell, MJ Clemens (2006) Cell Death and Diff. 12, 571-584.

  14. Message specific regulation of translation initiation

  15. IRE/IRP: steric hindrance IRE-IRBP Thomson et al. (1999) Intnl. J. Biochem & cell Biol. 31, pp 1139-1152.

  16. Sex-lethal: SXL Ann-Bin Shyu. Nature Struct. & Molec. Biol. (2006) 13, 189-190.

  17. Viral IRES X&Y=> IRES Trans-acting factors Stoneley and Willis (2004) Oncogene 23, 3200-3207

  18. IRES Mechanisms of Internal Initiation IRES

  19. Dicistronic Assay for IRES acitivity

  20. Cap-Independent Translation Initiation • Cellular • Cellular stress: viral infection (PKR), apoptosis, hypoxia • Normal cellular processes: G2/M phase cell cycle • Viral • Genomes: Picornaviruses, Hepatitis C Virus, Cricket paralysis virus • Specific viral messages: HIV, Herpes virus (…. and the list is still growing!)

  21. Cellular IRESes: How do they recruit 40S? • Widely assumed that the Secondary and tertiary Structure allow for interactions with translational machinery (ITAF,eIFs, 40S) • No common Structure • Composed of multiple short modules • Generally 150-300 nts long, exception: 9nt repeated element.

  22. mRNA-rRNA base-pairing Dresios et al. (2006) Nature Struct.& Mol. Bio. 13, 30-34.

  23. Summary • Mechanisms of initiation: • Cap-dependent translation • Cap-independent translation: Internal ribosome entry sites • Regulation of initiation: • Global • eIF2 alpha phosphorylation • 4E-BPs • Cleavage of eIF4G • Message specific • GCN4 • IRE/IRP • SXL • miRNA (microRNA)