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oai:drum.lib.umd.edu:1903/126582016-03-29T10:12:45Zcom_1903_11811com_1903_12com_1903_2col_1903_2750col_1903_3

Dinman, Jonathan D Belew, Ashton Trey Digital Repository at the University of Maryland University of Maryland (College Park, Md.) Cell Biology & Molecular Genetics 2012-07-07T05:51:02Z 2012-07-07T05:51:02Z 2012 http://hdl.handle.net/1903/12658 Although first discovered in viruses, previous studies have identified programmed -1 ribosomal frameshifting (-1 PRF) signals in eukaryotic genomic sequences, and suggested a role in mRNA stability. This work improves and extends the computational methods used to search for potential -1 PRF signals. It continues to examine four yeast -1 PRF signals and show that they promote significant mRNA destabilization through the nonsense mediated (NMD) and no-go (NGD) decay pathways. Yeast EST2 mRNA is highly unstable and contains up to five -1 PRF signals. Ablation of the -1 PRF signals or of NMD stabilizes this mRNA. These same computational methods identified an operational programmed -1 ribosomal frameshift (-1 PRF) signal in the human mRNA encoding CCR5. A -1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay (NMD) pathway. CCR5-mediated -1 PRF is stimulated by at least two miRNAs, one of which is shown to directly interact with the CCR5 -1 PRF signal. Structural analyses reveal a complex and dynamic mRNA structure in the -1 PRF signal, suggesting structural plasticity as the underlying biophysical basis for regulation of -1 PRF. Messenger RNA Destabilization by -1 Programmed Ribosomal Frameshifting Dissertation Cellular biology Bioinformatics Molecular biology Frameshifting mRNA Ribosome open.access