Poster abstracts
Poster number 2 submitted by Vivek Advani
Translational recoding in human disease: identifying the molecular pathologies underlying X-linked Dyskeratosis Congenita and Spinocerebellar Ataxia 26.
Vivek M Advani (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park MD 20742), Jonathan D. Dinman (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park MD 20742)
Abstract:
Gene expression can be controlled at the level of mRNA stability, and prior studies from our laboratory have explained how Programmed -1 Ribosomal Frameshifting (-1 PRF) fits within this paradigm. Computational analyses suggest that 10-15% of eukaryotic mRNAs contain at least one potential -1 PRF signal. The overwhelming majority of predicted “genomic” -1 PRF events would direct translating ribosomes to premature termination codons, and we have demonstrated that these can function as mRNA destabilizing elements through the Nonsense-Mediated mRNA Decay (NMD) pathway. In published work we have explored the biological significance of the connection between -1 PRF and NMD on telomere maintenance in yeast. More recently we extended this line of inquiry is to human cells, demonstrating that a sequence element in the mRNA encoding Ccr5p harbors a -1 PRF signal which functions as an mRNA destabilizing element through NMD. In the current work we are exploring the link between global changes in -1 PRF rates and human health using yeast and human cell-based models of two diseases, X-linked Dyskeratosis Congenita (X-DC) and Spinocerebellar ataxia 26 family (SCA26) as models. Preliminary findings suggest these genetically inherited defects result translational fidelity defects (i.e. changes in rates of -1 PRF, +1 PRF, and stop codon recognition), with attendant effects on mRNA abundance, gene expression and telomere maintenance. These studies establish a paradigm for understanding the linkage between translational fidelity and human disease.
Keywords: -1 PRF , NMD