Co-translational Polyamine Sensing by Nascent ODC Antizyme

Abstract

Polyamines are essential biogenic poly-cations with important roles in many cellular processes, including translation and DNA replication. High levels of polyamines have been linked to cancer. Increased levels of polyamines, however, have also been shown to promote longevity. Cellular regulation of polyamines involves a variety of complex mechanisms that regulate uptake and excretion as well as synthesis and catabolism of polyamines. A key enzyme in the biosynthesis of polyamines is ornithine decarboxylase (ODC). The activity and stability of this homodimeric protein is controlled by ODC antizyme (OAZ). OAZ binds ODC monomers and thereby targets them for ubiquitin-independent degradation by the proteasome. OAZ is encoded by an interrupted open reading frame. As a consequence, synthesis of the functional protein is slowed and only occurs when a ribosomal frameshift (RFS) event takes place. High polyamine concentrations lead to an increased efficiency of translation of OAZ mRNA. Our studies have revealed that nascent OAZ polypeptide causes a translational arrest of ribosomes when polyamine concentration is low. At higher concentrations, binding of polyamines to nascent OAZ prevents stalling of the ribosomes on OAZ mRNA and thereby promotes synthesis of full-length ODC antizyme. Co-translational sensing of polyamines thereby contributes to a homeostatic regulation of polyamine biosynthesis.