Figure 1.

Proposed disease-related mechanisms of CUG-expansions in DM1. Massive CUG-expansions in the 3′UTR of DMPK mRNA likely fold into a metastable hairpin structure (simplified here as a small number of CUG-repeats), which facilitates binding/sequestration of several factors including those depicted by colored circles/ovals. Examples of factors and the processes they affect (in parentheses) are presented. One important effect of this factor binding/sequestration is a misregulation of several specific splicing events causing adverse multisystemic phenotypes in affected individuals. TF = transcription factor. Mainly MBNL1 (green oval) is sequestered by CUG-hairpins, enhanced by the action of one or two of its interacting proteins, DEAD-box helicases DDX5/DDX17, which in turn promotes foci formation. DDX6 transiently interacts, unwinds the hairpin and potentially releases bound MBNL1 to allow for increased nuclear export and translation, which is also stimulated by Staufen 1 (Stau1). These proteins therefore likely counteract the function of DDX5. See text for references and further details.