1. The yeast prion [PSI+] Some references and information related to our research

2. Prion proteins - overview Prion are misshapen proteins that exist in at least two different conformations, one of which is self-replicating and expresses unique biological function  are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form ProteinPrionRemarks eRF3[PSI + ] Y east Saccharomyces cerevisiae Nucleus Normal Prion form Cell

3. [PSI + ] prion [PSI + ] is the prion form of the translational release factor eRF3, encoded by the chromosomal gene SUP35, which suppresses nonsense codons  conformational change impairs the termination activity of eRF3 increasing stop codon readthrough, resulting in the production of proteins with carboxy terminus extensions ORF AUG UAA Translation [psi - ][PSI + ] mRNA ORF AUG UAA C N C N C N Protein Decreased translational termination efficiency + UAA

4. [PSI + ] prion [PSI + ]-induced defect in translation termination could stimulate expression of frameshifted genes by affecting the reading frame maintenance of the ribosome, particularly if a codon particularly prone to allow +1 slippage is followed by a poorly recognized termination codon The only gene known to use a shifty-stop in yeast is the OAZ1 ORF1 AUG UGA ORF2 0 frame +1 frame OAZ1 frameshift site UAA 0 frame GCG UGA CAT CCC GCG GAC ATC CCT +1 frame eRF1 eRF3 Ribosome mRNA tRNA

5. Futher research: the yeast prion [PSI+] key references The latest from Susan Lindquist Whitehead Institute, Professor of Biology http://web.mit.edu/biology/www/facultyareas/facresearch/lindquist.html  Heather L. True & Susan L. Lindquist, A yeast prion provides a mechanism for genetic variation and phenotypic diversity NATURE,VOL 407, 28, 2000.  Cortland K. Griswold¤, Joanna Masel, Complex Adaptations Can Drive the Evolution of the Capacitor [PSI+], Even with Realistic Rates of Yeast Sex, PLoS Genet 5(6): e1000517. doi:10.1371/journal.pgen.1000517  Ivaylo P. Ivanov and John F. Atkins, Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation, 1842–1858 Nucleic Acids Research, 2007, Vol. 35, No. 6  Thomas Scheibel, Amyloid Formation of a Yeast Prion Determinant, Journal of Molecular Neuroscience 13 Volume 23, 2004  PAVEL V. BARANOV, RAYMOND F. GESTELAND, and JOHN F. ATKINS, P-site tRNA is a crucial initiator of ribosomal frameshifting, RNA (2004), 10:221–230  Thorsten Poschel, Nikolai V. Brilliantov, and Cornelius Frommel, Kinetics of Prion Growth, Biophysical Journal Volume 85 December 2003 3460–3474.

6. Yeast translation termination factor eRF3 research 1.Elongation factor eEF1B modulates functions of the release factors eRF1 and eRF3 and the efficiency of translation termination in yeast. Valouev IA, Fominov GV, Sokolova EE, Smirnov VN, Ter-Avanesyan MD. BMC Mol Biol. 2009 Jun 22;10:60.Elongation factor eEF1B modulates functions of the release factors eRF1 and eRF3 and the efficiency of translation termination in yeast. 2.Structural insights into eRF3 and stop codon recognition by eRF1. Cheng Z, Saito K, Pisarev AV, Wada M, Pisareva VP, Pestova TV, Gajda M, Round A, Kong C, Lim M, Nakamura Y, Svergun DI, Ito K, Song H. Genes Dev. 2009 May 1;23(9):1106-18.Structural insights into eRF3 and stop codon recognition by eRF1. 3.Prion: disease or relief? Chernoff YO. Nat Cell Biol. 2008 Sep;10(9):1019-21.Prion: disease or relief? 4.Distinct eRF3 requirements suggest alternate eRF1 conformations mediate peptide release during eukaryotic translation termination. Fan-Minogue H, Du M, Pisarev AV, Kallmeyer AK, Salas-Marco J, Keeling KM, Thompson SR, Pestova TV, Bedwell DM. Mol Cell. 2008 Jun 6;30(5):599-609.Distinct eRF3 requirements suggest alternate eRF1 conformations mediate peptide release during eukaryotic translation termination. 5.5. Mutation at tyrosine in AMLRY (GILRY like) motif of yeast eRF1 on nonsense codons suppression and binding affinity to eRF3. Akhmaloka, Susilowati PE, Subandi, Madayanti F. Int J Biol Sci. 2008 Apr 21;4(2):87-95.Mutation at tyrosine in AMLRY (GILRY like) motif of yeast eRF1 on nonsense codons suppression and binding affinity to eRF3. 6. Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases. Funakoshi Y, Doi Y, Hosoda N, Uchida N, Osawa M, Shimada I, Tsujimoto M, Suzuki T, Katada T, Hoshino S. Genes Dev. 2007 Dec 1;21(23):3135-48.Mechanism of mRNA deadenylation: evidence for a molecular interplay between translation termination factor eRF3 and mRNA deadenylases.