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.

Could global translation attenuation and cellular stress conditions permit RAN translation? (71) (72) (73) (74) . It is known that IRES-dependent translation occurs preferentially under cellular stress conditions such as growth, mitosis, apoptosis or viral infection, in which global cap-dependent translation is compromised (62) and is accompanied by the proteolysis of eIF4G and changes in the phosphorylation levels of eIF4E-binding proteins and eIF2A (24, 75) . Furthermore, stress might trigger post-translational modifications There are at least two translation initiation mechanisms: a canonical cap-dependent mechanism described in Eukaryotes and a cap-independent type IV IRES-dependent mechanism described in Dicistroviridae viruses. In the cap-dependent mechanism of translation initiation, the initiator tRNA is delivered to the ribosome as a ternary complex with eIF2 and GTP, and then, eIF1, eIF1A, eIF5 and eIF3 initiation factors promote binding to form a 43S pre-initiation complex. This complex binds to the mRNA through its interaction with the capbinding complex, which consists of eIF4E, eIF4G, eIF4A and eIF4B factors, and begins scanning for the start codon. In cap-independent/IRES-dependent translation initiation, highly structured type IV IRES, which does not require initiation factors, operates essentially as an all RNA-based ribosome recruitment apparatus; the IRES position of pseudoknot I mimics the initiator tRNA codon/anti-codon interaction that results in an initiation at the non-AUG codon. This type of translation initiation requires the interaction between IRES and ribosomal proteins RPS25 and RPS5. RAN translation is initiated by repeat-forming RNA structures. These structures could bind various proteins, including specific repeat binding proteins, translation initiation factors and other regulatory proteins. The riboprotein complex may resemble a translation initiation unit and trigger translation initiation in the absence of an AUG start codon. Thus, RAN translation might occur via a cap-dependent scanning mechanism (a) and/or as a result of IRES-like ribosome recruitment (b). In (a), the scanning ribosome approaches a repeat hairpin that results in the stalling of the pre-initiation complex. This forces an unspecific interaction between hairpin proteins and the pre-initiation complex and/or dissociation of some translation initiation factors that may result in noncanonical translation initiation at non-AUG codons . In (b) , a direct recruitment of the ribosome to hairpin-associated protein complex results in unspecific translation initiation, similar to what is proposed in (a), with the use of codons other than AUG.