Poster abstracts
Poster number 3 submitted by Vivek Advani
Establishing a link between Translational Recoding and Human Disease
Vivek M. Advani (Dept. of Cell Biology and Molecular Genetics, University of Maryland, College park), Ashton Trey Belew (Dept. of Cell Biology and Molecular Genetics, University of Maryland, College park), Jonathan D. Dinman (Dept. of Cell Biology and Molecular Genetics, University of Maryland, College park)
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(1). The overwhelming majority of predicted “genomic” -1 PRF events are predicted to direct translating ribosomes to premature termination codons. We have demonstrated that these can function as mRNA destabilizing elements through the Nonsense-Mediated mRNA Decay (NMD) pathway(2). In published work we have explored the biological significance of the connection between -1 PRF and NMD on telomere maintenance in yeast(3). More recently we extended this line of inquiry 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(4). 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 in 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.
References:
1. Belew AT et al. PRFdb: a database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals. BMC Genomics [Internet]. 2008 Jan [cited 2014 Oct 15];9(1):339.
2. Belew AT et al. Endogenous ribosomal frameshift signals operate as mRNA destabilizing elements through at least two molecular pathways in yeast. Nucleic Acids Res [Internet]. 2011 Apr 1 [cited 2014 Oct 14];39(7):2799–808.
3. Advani VM, Belew AT, Dinman JD. Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway. Transl (Austin, Tex) [Internet]. 2013 Apr 1 [cited 2014 Oct 14];1(1):e24418.
4. Belew AT et al. Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. Nature [Internet]. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2014 Jul 9 [cited 2014 Jul 9];512(7514):265–9.
Keywords: -1 PRF, translational fidelity, X-DC