ESTABLISHING LINK BETWEEN TRANSLATIONAL RECODING AND HUMAN DISEASE
| dc.contributor.advisor | Dinman, Jonathan D | en_US |
| dc.contributor.author | Advani, Vivek Manoharlal | en_US |
| dc.contributor.department | Cell Biology & Molecular Genetics | en_US |
| dc.contributor.publisher | Digital Repository at the University of Maryland | en_US |
| dc.contributor.publisher | University of Maryland (College Park, Md.) | en_US |
| dc.date.accessioned | 2015-06-26T05:44:55Z | |
| dc.date.available | 2015-06-26T05:44:55Z | |
| dc.date.issued | 2015 | en_US |
| dc.description.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 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. 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 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 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. | en_US |
| dc.identifier | https://doi.org/10.13016/M2FP6V | |
| dc.identifier.uri | http://hdl.handle.net/1903/16670 | |
| dc.language.iso | en | en_US |
| dc.subject.pqcontrolled | Molecular biology | en_US |
| dc.subject.pquncontrolled | -1 PRF | en_US |
| dc.subject.pquncontrolled | NMD | en_US |
| dc.subject.pquncontrolled | Recoding | en_US |
| dc.subject.pquncontrolled | Ribosomopathies | en_US |
| dc.title | ESTABLISHING LINK BETWEEN TRANSLATIONAL RECODING AND HUMAN DISEASE | en_US |
| dc.type | Dissertation | en_US |
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