The termination of translation at all nonsense codons is a crucial step in the transition from gene to functional product, and both genetic and epigenetic factors influence the fidelity of this process in vivo. This regulatory network produces a dynamic range of termination efficiencies in vivo that is exploited by the cell to regulate mRNA stability, translation efficiency, and perhaps genomic evolution. The termination of translation is, therefore, not simply a static end to protein synthesis but, rather, an influential and largely uncharacterized regulator of gene expression in eukaryotes. The long-term goal of my laboratory is to understand the molecular basis of this flexibility and its physiological consequences. One target of these regulatory processes in the yeast Saccharomyces cerevisiae is the Sup35 protein, a component of the translation termination apparatus and a member of the growing family of prion proteins. Sup35 adopts multiple, self-replicating physical forms in vivo, each of which confers a distinct level of termination efficiency on the cell. Since these conformers are epigenetic in nature, their associated functional states are stably inherited but fully and rapidly interconvertible. Using a variety of approaches in vivo and in vitro, we are investigating the protein-state dynamics that underlie regulated transitions between these physical and functional forms. These studies will provide mechanistic insight into the regulation of translation termination by the Sup35 prion cycle as well as the progression of mammalian diseases linked to similar self-perpetuating changes in protein physical state, such as the transmissible spongiform encephalopathies (i.e. mad cow disease), Alzheimer’s Disease, Huntington’s Disease, and Parkinson’s Disease.