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 exact sites of RAN translation initiation at expansions of CAG, CGG, G 4 C 2 and C 4 G 2 repeats are unknown and may differ among repeats and reading frames. For CAG repeats in SCA8, RAN translation in the polyGln frame initiates at or near the start of the repeats, independently of an upstream AUG codon, whereas in the GCA frame encoding polyAla, it initiates at various sites throughout the length of the repeats (14) . For CGG repeats in FXTAS, this atypical translation was shown to start between the 21st and 12th nucleotide 5 of the repeats for the polyGly reading frame, was sensitive to stop codons when placed just proximal to the repeats and required an upstream AUG-like codon such as GUG. By contrast, polyAla formation arose independently of AUG-like codons and was insensitive to stop codon insertion 5 of the repeats (16) . For G 4 C 2 hexanucleotides in C9ALS/FTD, the exact start of RAN translation is also unknown, but its termination does not necessarily occur on the repeats. As it has been demonstrated for polyGlyAla and polyGlyArg frames, at least a fraction of RAN translation products are extended beyond the repeats into the 3 region (22) . Consequently, the length of some RAN-translated proteins may depend on the position of the stop codon in a particular frame.