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Epigenetic control of polyamines by the prion [PSI+]

Abstract

Prion proteins are found in mammals and yeast, and can transmit diseases and encode heritable phenotypic traits1. In Saccharomyces cerevisiae, eRF3, Rnq1, Ure2 and Swi1 are functional proteins with a soluble conformation that can switch to a non-functional, amyloid conformation denoted as [PSI+], [PIN+], [URE3] and [SWI+], respectively2,3. The prion [PSI+] corresponds to an aggregated conformation of the translational release factor eRF3, which suppresses nonsense codons2. [PSI+] modifies cellular fitness and induces several phenotypes according to the genetic background4,5. An elegant series of studies has demonstrated that several [PSI+]-induced phenotypes occur as a consequence of decreased translational termination efficiency6,7. However, the genes whose expression levels are controlled by [PSI+] remain largely unknown. Here, we show that [PSI+] enhances expression of antizyme, a negative regulator of cellular polyamines, by modulating the +1 frameshifting required for its expression8. Our study also demonstrates that [PSI+] greatly affects cellular polyamines in yeast. We show that modification of the cellular content of polyamines by the prion accounts for half of the [PSI+]-induced phenotypes. Antizyme is the first protein to be described for which expression in its functional form is stimulated by [PSI+].

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Figure 1: [PSI+] effects on recoding events.
Figure 2: Quantification of intracellular polyamine levels in [psi] and [PSI+] strains.
Figure 3: [PSI+]-induced phenotypes.
Figure 4: Schematic representation of polyamine regulation by [PSI+].

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Acknowledgements

We thank Hiroko Takizawa for technical assistance. English usage was corrected by Alex Edelman & Associates. This work was supported by grants from the Agence Nationale pour la Recherche to J.P.R. (ANR-06-BLAN-0391-01), the Association Pour la Recherche sur le Cancer to J.P.R. (Contract 3849) and by grants-in-aid to S.M. from the Ministry of Education, Sports, Culture, Science and Technology of Japan. O.N. was funded by a fellowship from the ARC for part of this study. A.G. is funded by a fellowship from the French Ministry of Education and Research (MENESR).

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O.N. developed the hypothesis and conceived the experiments; A.G. and O.N. constructed the OAZ yeast strain derivative and quantified recoding events. C.M. tested the [PSI+]-dependent phenotypes and performed the western blot analysis. C.F. constructed the plasmid overexpressing SUP35 to induce the shift from [psi] to [PSI+]. S.M. performed HPLC experiments to quantify polyamine levels in yeast strains. J.P.R. coordinated the study. All authors discussed the results and contributed to the writing of this manuscript.

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Correspondence to Olivier Namy.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures S1, S2, S3 and Supplementary Table S1 (PDF 451 kb)

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Namy, O., Galopier, A., Martini, C. et al. Epigenetic control of polyamines by the prion [PSI+]. Nat Cell Biol 10, 1069–1075 (2008). https://doi.org/10.1038/ncb1766

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