Messenger RNA Decay in Muscle and
Myotonic Dystrophy

Myotonic dystrophy is an inherited disease caused by a triplet repeat expansion in non-coding regions of the affected gene. When transcribed, the repeat-containing RNAs are toxic to the cell and accumulate in nuclear foci where they sequester cellular proteins (Fig. 1.). The sequestered factors are unable to perform their normal functions. Two proteins affected by the toxic RNA are Muscleblind (MBNL) which binds directly to the expanded repeat RNAs and CUGBP1/CELF1 which is over-expressed and aberrantly localized through an uncharacterized mechanism. Altered or impaired function of CUGBP1 and MBNL has been linked with defects splicing of clinically relevant mRNAs in myotonic dystrophy (Dickson & Wilusz, 2010).

However, CUGBP1 has also been implicated as a modulator of many steps in mRNA metabolism including mRNA decay. We showed previously that CUGBP1 can recruit a deadenylase called PARN to destabilize RNAs in vitro vitro (Moraes et al, 2006). Moreover, we have shown that depletion of CUGBP1, or expression of expanded repeat containing RNAs, results in stabilization of the TNF mRNA in mouse muscle cells (Zhang et al, 2008). We believe that some symptoms of myotonic dystrophy may be linked with stabilization of mRNAs due to altered function of CUGBP1. We have identified novel targets of CUGBP1 that encode proteins essential for muscle cell differentiation and protein secretion (Lee et al 2010).

Current projects in the lab are funded by an R01 from NIH-NIAMS and focus on determining how mRNA stability is changed in myotonic dystrophy patient cells as well as elucidating the mechanism of decay of the toxic DMPK mRNA. We are also investigating the roles of CUGBP1 and PARN in normal muscle cells. Our recent results have suggested that PARN may be an important regulator of the extracellular matrix and cell migration in muscle cells (Lee et al 2012).