Messenger RNA Decay in Muscle and
|Dr Alexa Dickson PhD||Post-doctoral Fellow|
|Dr Mary Schneider, PhD||Post-doctoral Fellow|
|Dr Stephen Coleman, PhD||Post-doctoral Fellow|
|Annie Zhang||CMB Graduate Student|
|Tori Taillac||Undergraduate Research Assistant|
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).
Lee, JE, Lee JY, Wilusz J, Tian, B & Wilusz CJ (2010) Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells. PLoS One. 2010 Jun 21;5(6):e11201
Zhang L, Lee JE, Wilusz J, Wilusz CJ. (2008) The RNA-binding protein CUGBP1 regulates stability of tumor necrosis factor mRNA in muscle cells: implications for myotonic dystrophy. J Biol Chem. 283:22457-63
Andy Berglund - University of Oregon
David Brook - University of Nottingham
Pascale Chartrand - University of Montreal
Tom Cooper - Baylor College of Medicine
Ralph Krahe - MD Anderson Cancer Center
Mani Mahadevan - University of Virginia
Glenn Morris - Wolfson Center for Inherited Neuromuscular Disease
Jack Puymirat - University of Laval
Laura Ranum - University of Minnesota
Sita Reddy - Keck School of Medicine of USC
Maurice Swanson - University of Florida
Charles Thornton - University of Rochester Medical Center
Lubov Timchenko - Baylor College of Medicine