Mechanisms of polyamine-dependent control of ornithine decarboxylase and its antizyme

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Polyamines are essential organic cations with a variety of cellular functions. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in the biosynthesis of polyamines. ODC turnover is the paradigm of ubiquitin-independent proteolysis. Both in mammals and lower eukaryotes, ODC degradation is induced by high levels of polyamines, which thus constitutes a regulatory feedback control of polyamine biosynthesis. Work in mammals has revealed a mechanism wherein polyamines induce a ribosomal frameshifting during the decoding of an mRNA encoding ODC antizyme. This protein mediates degradation of ODC by the proteasome. We have discovered an ODC antizyme, termed Oaz1, in Saccharomyces cerevisiae that has long escaped detection due to its low but significant sequence similarity to mammalian antizymes. Oaz1 synthesis is controlled by polyamine-induced ribosomal frameshifting. Using the yeast model system we moreover discovered that Oaz1 levels are in addition controlled by ubiquitin-mediated proteolysis. Degradation of Oaz1 is inhibited by polyamines. In this project, we want to characterize the mechanisms that underlie polyamine-induced ribosomal frameshifting during decoding of OAZ1 mRNA and to characterize the principles of ubiquitinmediated proteolysis of Oaz1 and how this process is inhibited by polyamines. These studies are likely to be relevant for an understanding of the regulation of polyamine biosynthesis in higher organisms including humans as well.