Talk on Saturday 09:15-09:30am submitted by Vivek Advani
Translational recoding in Human Disease
Vivek Advani (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park), Mary McMahon (Department of Urology, University of California, San Francisco), Jordan Aoyama (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park), Joesph Briggs (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park), Davide Ruggero (Department of Urology, University of California, San Francisco), Jonathan D. Dinman (Department of Cell Biology and Molecular Genetics, University of Maryland, College Park)
Translational recoding has recently emerged as an important mechanism of post-transcriptional gene regulation. Prior studies have explained how Programmed -1 Ribosomal Frameshifting (-1 PRF) fits within this paradigm. Analysis of predicted -1 PRF signals across 20 genomes suggests that it is a universal mechanism(1). The overwhelming majority of “genomic” -1 PRF events are predicted to direct translating ribosomes to premature termination. These -1 PRF signals function as mRNA destabilizing elements through the Nonsense-Mediated mRNA Decay (NMD) pathway(2)(3). We have explored the significance of the connection between -1 PRF and NMD on telomere maintenance in yeast(4). In published work we have shown that human mRNA encoding Ccr5p harbors a -1 PRF signal which functions as an mRNA destabilizing element through NMD(5). In the current work we are exploring how abnormalities in ribosome function, implicated in congenital and acquired syndromes, broadly classified as ‘ribosomopathies’, contribute to disease pathogenesis. Preliminary findings using X-linked Dyskeratosis Congenita (X-DC) and Spinocerebellar ataxia 26 family (SCA26) as models suggest that these genetically inherited defects result in translational fidelity defects (i.e. changes in rates of -1 PRF, +1 PRF, stop codon recognition), with attendant effects on mRNA abundance and gene expression. The observations that global dysregulation of -1 PRF has deleterious effects on gene expression leads us to hypothesize that ‘-1 PRF plays an important role in regulating cellular gene expression’. In silico analysis predicts ~10% of the genes in humans have at least one functional -1 PRF signal which translates to 1,943 high probability candidates in the human genome. Through Found in Translation (FIT) Undergraduate Research Program, we have validated -1 PRF signals encoded by over 70 human genes involved in immune signaling, cancer, anemias and other diseases.
1. Belew AT et.al. PRFdb: a database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals. BMC Genomics 2008 Jan.
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.2010 Nov;39 2799–808.
3. Plant EP et.al. A programmed -1 ribosomal frameshift signal can function as a cis-acting mRNA destabilizing element. Nucleic Acids Res. 2004 Jan 3 32(2):784–90.
4. Advani VM et.al. Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway. Transl. 2013 Apr 1
5. Belew AT et.al. Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. Nature. 2014;512:265–9
Keywords: Translational Recoding, -1 PRF, Ribosomopathies