Creating a protein-based element of inheritance.

Proteins capable of self-perpetuating changes in conformation and function (known as prions) can serve as genetic elements. To test whether novel prions could be created by recombinant methods, a yeast prion determinant was fused to the rat glucocorticoid receptor. The fusion protein existed in different heritable functional states, switched between states at a low spontaneous rate, and could be induced to switch by experimental manipulations. The complete change in phenotype achieved by transferring a prion determinant from one protein to another confirms the protein-only nature of prion inheritance and establishes a mechanism for engineering heritable changes in phenotype that should be broadly applicable.

[1]  S. Lindquist,et al.  Self-Seeded Fibers Formed by Sup35, the Protein Determinant of [PSI +], a Heritable Prion-like Factor of S. cerevisiae , 1997, Cell.

[2]  R. Wickner,et al.  The prion model for [URE3] of yeast: spontaneous generation and requirements for propagation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Harrison,et al.  Characterization of a monoclonal antibody to the rat liver glucocorticoid receptor. , 1984, Endocrinology.

[4]  V. Smirnov,et al.  The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae. , 1994, Genetics.

[5]  L. Kisselev,et al.  Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. , 1995, The EMBO journal.

[6]  K. Yamamoto,et al.  Mammalian glucocorticoid receptor derivatives enhance transcription in yeast. , 1988, Science.

[7]  D. Thiele.  ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene , 1988, Molecular and cellular biology.

[8]  I. Stansfield,et al.  The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. , 1995, The EMBO journal.

[9]  R. Wickner,et al.  [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. , 1994, Science.

[10]  Stanley B. Prusiner,et al.  Nobel Lecture: Prions , 1998 .

[11]  F. Lacroute.  Non-Mendelian Mutation Allowing Ureidosuccinic Acid Uptake in Yeast , 1971, Journal of bacteriology.

[12]  K. Wüthrich,et al.  Prion-inducing domain 2-114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Y. Chernoff,et al.  Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non‐overlapping functional regions in the encoded protein , 1993, Molecular microbiology.

[14]  J R Glover,et al.  Support for the Prion Hypothesis for Inheritance of a Phenotypic Trait in Yeast , 1996, Science.

[15]  S W Liebman,et al.  Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. , 1995, Science.

[16]  A. Surguchov,et al.  Nucleotide sequence of the SUP2 (SUP35) gene of Saccharomyces cerevisiae. , 1988, Gene.

[17]  Y. Chernoff,et al.  Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. , 1996, Genetics.

[18]  M. Tuite,et al.  Agents that cause a high frequency of genetic change from [psi+] to [psi-] in Saccharomyces cerevisiae. , 1981, Genetics.

[19]  S. Lindquist,et al.  Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast , 1999, Nature.