Molecular mechanisms in DM1 - a focus on foci

Abstract

Myotonic dystrophy type 1 is caused by abnormal expansion of a CTG-trinucleotide repeat in the gene encoding Dystrophia Myotonica Protein Kinase (DMPK), which in turn leads to global deregulation of gene expression in affected individuals. The transcribed mRNA contains a massive CUG-expansion in the 3' untranslated region (3'UTR) facilitating nucleation of several regulatory RNA-binding proteins, which are thus unable to perform their normal cellular function. These CUG-expanded mRNA-protein aggregates form distinct, primarily nuclear foci. In differentiated muscle cells, most of the CUG-expanded RNA remains in the nuclear compartment, while in dividing cells such as fibroblasts a considerable fraction of the mutant RNA reaches the cytoplasm, consistent with findings that both nuclear and cytoplasmic events are mis-regulated in DM1. Recent evidence suggests that the nuclear aggregates, or ribonuclear foci, are more dynamic than previously anticipated and regulated by several proteins, including RNA helicases. In this review, we focus on the homeostasis of DMPK mRNA foci and discuss how their dynamic regulation may affect disease-causing mechanisms in DM1.

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.

Figure 2.

CUG-foci visualized by RNA-fluorescence in-situ hybridization. CUG-expanded DMPK mRNA accumulates in distinct foci in DM1 patient cells (red foci indicated at the tip of white arrows and enlarged in inset). Blue color indicates nucleus (DAPI staining).

Figure 3.

Two-state model of CUG-expansions in foci or diffuse states. DDX5 and DDX6 exert opposite effects on CUG-foci potentially by promoting (DDX5) or restricting (DDX6) MBNL1 binding to CUG-repeats allowing for dynamic changes between a focal/insoluble state and a diffuse/soluble state (see text for further details).