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.

Because the precise involvement of RNA structures in RAN translation needs further investigation, the question has arisen whether these repeat sequences act as IRES to initiate RAN translation via a cap-independent mechanism. Such a scenario was suggested because hairpin-and G-quadruplex-forming repeats might mimic IRES structures, and the 5 region preceding the CGG repeats of the FMR1 transcript had previously been identified to function as an IRES and a site of ribosome pausing (48) . Based on such factors as dependence on canonical eukaryotic initiation factors (eIFs), the proposed secondary structure, start codon localization and ability of the IRES to function in a cell-free system with or without supplementa-Nucleic Acids Research, 2014, Vol. 42, No. 19 11853 tion, known viral IRES were divided into four groups. Initiation on types I and II typically requires most canonical initiation factors including eIF3, eIF4A and the Cterminal domain of eIF4G in addition to the eIF2-Met-tRNA i Met -GTP ternary complex. In contrast, type III IRES directly attach the 43S complex to the initiation codon independently of eIF4F, eIF4B, eIF1 and eIF1, whereas type IV IRES initiate without eIFs or Met-tRNA i Met (49, 50) . Of the four known IRES-initiated translation mechanisms used by viruses, only type IV is both cap-independent and AUG-independent and thus could explain certain features of RAN translation initiation. The three other types of viral IRES mechanisms require an AUG codon and thus fail to explain why RAN translation produces proteins in multiple frames. With all these uncertainties, it seems that an alternative, as yet unknown mechanism may govern translation initiation at expanded RNA repeats.