Figure 2. STR-associated toxicity in Repeat Expansion Disorders.

Repeat expansions can alter global 3D chromatin structure, and influence transcription via blocking or enhancing binding of nucleosomes, (de)acetylases, (de)methylases, and transcription factors. Expanded repeats may also impede polymerase processivity. In some cases, elevated transcription of repeat expansion RNA can lead to depletion of RNA-binding proteins. Depletion of these proteins can impact many processes to which they contribute, including pre-mRNA splicing and processing, and mRNA localization. Expanded repeat RNA and bound RBPs can also aggregate into RNA foci, causing toxicity. Expanded repeat RNA can stall translational complexes, leading to repeat-associated non-AUG (RAN) translation, and contribute to the production of polymeric proteins. Polymeric proteins are aggregate prone. Longer polymeric stretches in native proteins may also cause dysfunction by preventing proper protein folding or causing the folded protein to mis-localize within the cell.