RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders

Wojciechowska, Marzena; Olejniczak, Marta; Galka-Marciniak, Paulina; Jazurek, Magdalena; Krzyzosiak, Wlodzimierz J.

Programmed ribosomal frameshifting (PRF) is a common mechanism that increases the protein-coding capacity of small genomes such as viruses and mitochondria. Frameshifting events were also observed in the case of some mammalian genes (82, 83) . Three elements within mRNA have been shown to be required for the efficient induction of (−1) PRF: a 7-nt slippery sequence (84), a short 5-12 nt spacer and a stimulatory structure that can be a pseudoknot, hairpin structure, G-quadruplex (85) (86) (87) (88) (89) or mRNA duplex formed with the antisense oligonucleotide (90) . The nature of the slippery sequence facilitates slippage of the tRNAs within the P and A sites on the mRNA, whereas the stimulatory structure provides an energetic barrier that causes an elongating ribosome to pause on the slippery sequence. Several models have been proposed to explain the mechanism of (−1) PRF (91) (92) (93) (94) , and it seems that structural elements of mRNA play an important role in this process, e.g. the stability of the first 3 or 4 bp at the base of the hairpin stem was shown to be critical for shifting the ribosome by these structures (87, 95) . Jacks et al. proposed 'the two tRNA simultaneous slippage model,' in which the shift occurs after delivery of the aa-tRNA to the A site but before peptidyl transfer (91) . A downstream stimulatory motif inhibits the EF2-driven movement of the ribosome. The resulting tension is relieved by unpairing of the aa-tRNA and peptidyl-tRNAs from the mRNA, slipping of the mRNA by one base and re-pairing of the tRNAs in the (−1) frame (91, 92, 96) . A second model proposed by Weiss et al. assumes that (−1) PRF occurs during the translocation step (85, 97) . Briefly, after peptide bond formation, the deacetylated-tRNA and the peptidyl-tRNAs occupy, respectively, the P/E and A/P sites. They can unpair from the mRNA due to the physical barrier formed by the stimulatory structure, move, and re-pair in the new reading frame. In the third model, the (−1) PRF is triggered by incomplete translocation and depends on the interactions of tRNAs with the A, P and E sites on the ribosome (93) .