RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders.
Bottom Line: Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively.The contribution of unusual translation products to pathogenesis needs to be better understood.In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.
Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.Show MeSH
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Mentions: It remains to be established whether frameshifting on CAG repeats results from an incomplete 2-base translocation event ((+2) frameshifting) or ribosome slippage by one base in the 5′ direction ((−1) frameshifting). Both these processes generate the same GCA frame encoding alanine; however, different nomenclature used by the authors may be confusing. Because frameshifting has been shown to occur in both SCA3 and HD, the most straightforward explanation is that the CAG repeat sequences of, respectively, ATXN3 and HTT are particularly susceptible to such repositions of reading frames, as experimental evidence demonstrated a higher frequency of frameshifting on longer repeats of both transcripts (26,28–30). However, as the structural requirements of RNA that induce frameshifting are not sufficiently known, it seems plausible that the hairpin structures formed by elongated CAG repeats of ATXN3 and HTT (Figure 3) (98–100) may serve as frameshifting stimulatory sequences, leading to ribosome pausing (Figure 4). Pseudoknots are a common type of stimulatory motif, but hairpin structures are also used by some viruses, e.g. HIV-1 (101,102). During translation elongation on expanded CAG repeat tracts, multiple hairpin structures may fold and unfold by moving the ribosomal complex. In investigating mechanisms of ribosomal frameshifting within repeated sequences, it would be interesting to determine whether the influence of CAA interruptions which are known to alter structure of CAG repeat hairpins (57) affects the frameshifting frequency.
Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.