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.

The sequences adjacent to repeats may affect the RAN translation ability or efficiency, as demonstrated by Ranum et al., who used HEK293T cells transfected with constructs containing 20 bp of the 5 endogenous flanking sequence upstream of the CAG repeats at the HD, HDL2, DM1 and SCA3 loci (14) . In this system, the products of RAN translation in the polyGln frame, which were abundant in the SCA8 context, were expressed at lower levels in the HD, HDL2, SCA3 and DM1 sequence contexts. In addition, the process of RAN translation of these constructs appeared to be less prevalent when studied in the cell-free rabbit reticulocyte lysate system, indicating specific protein requirements. When tested in a noncellular environment, RAN translation was also shown to be sensitive to the presence of alternative start codons (14) . Together, these results suggest the importance of particular RNA structures, AUGlike codons and specific cellular proteins for RAN translation, whose efficiency varies for repeats occurring in different gene contexts and cellular habitats.