Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation

Abstract

The protein antizyme is a negative regulator of intracellular polyamine levels. Ribosomes synthesizing antizyme start in one ORF and at the codon 5′ adjacent to its stop codon, shift +1 to a second and partially overlapping ORF which encodes most of the protein. The ribosomal frameshifting is a sensor and effector of an autoregulatory circuit which is conserved in animals, fungi and protists. Stimulatory signals encoded 5′ and 3′ of the shift site act to program the frameshifting. Despite overall conservation, many individual branches have evolved specific features surrounding the frameshift site. Among these are RNA pseudoknots, RNA stem-loops, conserved primary RNA sequences, nascent peptide sequences and branch-specific ‘shifty’ codons.

Organisation of human ER-exit sites: requirements for the localisation of Sec16 to transitional ER

“…Notably, five out of six of these inserts were out of frame, yet showed a strong and specific interaction with the CCD of Sec16A, and activated all reporters in the system. This is probably due to frameshifting during translation in yeast, which has been previously described (FromontRacine et al, 1997;Ivanov and Atkins, 2007). We confirmed this interaction by re-cloning the coding region of only Sec13.…”

uORFs with unusual translational start codons autoregulate expression of eukaryotic ornithine decarboxylase homologs

“…The comparable situation in plant S-adenosylmethionine decarboxylase 5Ј leaders, which have evolved independently from vertebrates, may be even more relevant because initiation of the first of two highly conserved uORFs may be influenced by polyamine-dependent leaky scanning (16). Yet another example of translational autoregulation in genes influencing polyamine synthesis is the programmed ribosomal frameshifting required for antizyme synthesis acting as a sensor of polyamine levels (34,35).…”

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

“…Az inhibits cell proliferation and displays antitumor activity, and therefore, it is regarded as a tumor suppressor (12)(13)(14)(15). Mammalian cells express three characterized members of the Az family of proteins (6,16). While one of them, Az3, is testis-specific and observed only in haploid germinal cells (17,18), the other two, the prototypical Az1 and Az2, are ubiquitously expressed, with Az1 being expressed at much higher levels (5,6,19).…”