Absconding with the threesome

Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. The patients have an expansion of a CUG-repeat in the 3′UTR of an mRNA encoding a protein kinase (DMPK). Triplet repeat expansions cause a number of human diseases, and their mechanisms of action vary in different diseases. Two independent studies performed to elucidate the mechanism that causes defects in muscle of DM patients now show that a CUG-binding protein (CUGBP1) might be involved and that long CUG-repeats in RNA alone are insufficient for the regeneration defect in muscle1xMolecular basis for impaired muscle differentiation in myotonic dystrophy. Timchenko, N.A. et al. Mol. Cell. Biol. 2001; 21: 6927–6938Crossref | PubMed | Scopus (112)See all References, 2xThe myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Amack, J.D. and Mahadevan, M.S. Hum. Mol. Genet. 2001; 10: 1879–1887Crossref | PubMedSee all References.Timchenko and colleagues, using myoblasts isolated from DM patients and normal individuals, show that the DM-myoblasts are differentiation defective and can re-enter cell cycle after ‘differentiation’, in contrast to normal myoblasts, which irreversibly arrest1xMolecular basis for impaired muscle differentiation in myotonic dystrophy. Timchenko, N.A. et al. Mol. Cell. Biol. 2001; 21: 6927–6938Crossref | PubMed | Scopus (112)See all References1. They further show that this defect is due to the inability of these cells to upregulate p21 (Cip1) protein, a cyclin-dependent kinase (CDK) inhibitor essential for irreversible arrest upon myoblast differentiation. Interestingly, the CUG binding activity, which increases in the cytoplasm as normal myoblasts differentiate, is undetectable in the cytoplasm of differentiating DM myoblasts. At the same time, the levels build up in the nucleus as a function of the number of CUG repeats present in the DMPK gene of patients. After correlating the absence of p21 in differentiating DM myoblasts with the levels of cytoplasmic CUGBP1, the authors provide evidence for the latter's role in translational activation of p21 mRNA dependent on a short GCN-rich sequence in the 5′ region of the p21 mRNA.In independent experiments conducted on a mouse myoblast cell line transfected with different green-fluorescent protein (GFP) constructs with CUG repeats in their 3′UTRs, Amack and Mahadevan uncouple the accumulation of nuclear (and cytoplasmic in this case) foci of CUG-repeat-RNA from defects in differentiation. They show that myoblasts with only parts of a mut-3′UTR (an expanded DMPK 3′UTR) in the GFP minigene differentiate normally – unlike myoblasts with the GFP–complete-mut 3′UTR construct – although all form RNA foci in the nucleus and cytoplasm2xThe myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Amack, J.D. and Mahadevan, M.S. Hum. Mol. Genet. 2001; 10: 1879–1887Crossref | PubMedSee all References2. This indicates that the formation of foci (which depends only on CUG expansion) is not sufficient for the differentiation defects and that other regions of the DMPK 3′UTR might be important in this process.Although there are some discrepancies between the observations of the two groups, probably owing to the differences in the source of myoblasts, some tentative conclusions can be drawn. In particular, if mislocalization of CUGBP1 is the cause for the differentiation defect in diseased myoblasts, then, for the nuclear retention of this protein, CUG-repeats alone are not sufficient – rather, the CUG-repeats in the context of other sequence motifs in the 3′UTR of DMPK are essential.