Room: B407 Microbiology
Our laboratory studies the regulation of mRNA metabolism in eukaryotic cells. Specifically, we are investigating the role of aspects of mRNA metabolism in pathogenesis of human disease. Our interests range from genetic diseases such as myotonic dystrophy, to cancer, to viral infections. Much of the work in the lab is done in collaboration with Dr Jeffrey Wilusz.
We are interested in a potential contribution of aberrant mRNA decay to the pathogenesis of Myotonic Dystrophy. Myotonic Dystrophy, DM1, is caused by an expanded CTG repeat in the 3'UTR of the myotonic dystrophy protein kinase (DMPK; Brook et al., 1992). This repeat is transcribed into the mRNA where it causes retention of the transcript in nuclear foci (Taneja et al., 1995). One consequence of this is reduced expression of DMPK. However, this defect is not the major cause of disease. The RNA itself is toxic to the cell and induces several characterized alterations in muscle-specific gene expression (Ranum and Day, 2004).
One protein whose expression is dramatically affected in DM1 patients is CELF1/CUGBP1 (Roberts et al., 1997). CELF1 is an RNA-binding protein implicated in several altered mRNA splicing events in DM1 cells(Philips et al., 1998). In addition, CUG-BP has been shown to modulate translation of clinically relevant mRNAs (Timchenko et al., 2004; Welm et al., 2000). Our laboratory demonstrated that CELF1 is able to enhance shortening of the poly(A) tail of certain mRNAs by the PARN deadenylase in vitro (Moraes et al., 2006). As the poly(A) tail normally acts to promote translation and prevent mRNA decay, this may indicate that mis-expression of CELF1 plays an integral role in altering decay of certain mRNAs in DM1 patients. In collaboration with Dr Bin Tian at NJ Medical School, we used global approaches to identify novel targets of CELF1 in muscle cells (Lee et al 2010). Importantly, mRNAs encoding proteins important for muscle differentiation and cell cycle are regulated by CELF1. We are now working to determine whether changes in stability of such transcripts may be responsible for pathogenesis in DM1.
This work is funded by the NIH-NIAMS
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 5:e11201. PMID: 20574513
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. PMID: 18559347
Garneau N.L., Wilusz J, Wilusz C.J. (2007). The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 2:113-26.