Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

The positively charged low molecular weight diamines and polyamines, putrescine, spermidine and spermine, occur in all cells. They play crucial roles in ion channels and many biochemical processes including transcription and translation ( Figure 7 ). Not surprisingly, they have disease relevance (260) . The over 80 000 publications listed in Pubmed are a reflection of the level of interest they have attracted. Though elevated levels occur in cancer cells, their levels are normally tightly controlled. A key regulator of intracellular polyamine levels is the protein antizyme whose existence was initially postulated as an 'anti-enzyme' inhibitor of ornithine decarboxylase that catalyzes the synthesis of putrescine from which spermidine and ultimately spermine are derived (261) . Despite considerable skepticism about the reality of its existence, and practical difficulties, a mammalian antizyme gene was cloned. Two partially overlapping reading frames were identified, and the protein sequence encoded by the frame junction region was determined (262, 263) . Not only is +1 frameshift- Figure 7 . Schematic representation of synthesis of mammalian antizyme-1 (AZ) protein and the interactions between it, ornithine decarboxylase (ODC), antizyme inhibitor (AZ Inhib), ATP citrate lyase (ACYL) and polyamine transporters. Increasing polyamines enhances the ribosomal frameshifting required for synthesis of antizyme, which then acts to inhibit synthesis and uptake of polyamines. Antizyme binding to an ODC monomer prevents the ODC dimer formation required for catalyzing synthesis of putrescine from which the polyamines spermidine and spermine are derived.