Sensing, Shiftingand Degradation: Regulation ofpolyamine biosynthesis by novel mechanisms

Polyamines are essential organic polycations withmultiple cellular functions relevant for cell division, cancer and ageing.Regulation of polyamine synthesis is mainly achieved by controlling theactivity of ornithine decarboxylase (ODC) through an unusual mechanisminvolving ODC antizyme, the binding of which disrupts homo- dimeric ODC andtargets it for ubiquitin-independent degradation by the 26S proteasome. Whereasmammals express several antizyme genes, we have identified a single orthologue,termed OAZ1, in Saccharomyces cerevisiae. Similar to its mammaliancounterparts, OAZ1 synthesis is induced with rising intracellular polyamineconcentrations, which also inhibit ubiquitin-dependent degradation of the OAZ1protein. Together, these mechanisms contribute to a homeostatic feedbackregulation of polyamines. Antizyme synthesis involves a conserved +1 ribosomalframeshifting (RFS) event at an internal STOP codon during decoding of itsmessenger RNA. By using S. cerevisiae OAZ1 we found that the nascent antizymepolypeptide is the relevant polyamine sensor that operates in cis to negatively regulate upstream RFS on the polysomes, whereits own mRNA is being translated. Our study revealed a conceptually novelautoregulatory mechanism, in which binding of a small metabolite to a nascentsensor protein stimulates the latter’s synthesis co-translationally. During thetalk I will explain how these novel mechanisms constitute the complex polyaminehomeostasis in the cell.