Dissertation/Thesis Abstract

Messenger RNA destabilization by -1 programmed ribosomal frameshifting
by Belew, Ashton Trey, Ph.D., University of Maryland, College Park, 2012, 198; 3517637
Abstract (Summary)

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.

Indexing (document details)
Advisor: Dinman, Jonathan D.
Commitee: Cummings, Michael P., Kahn, Jason D., Mount, Stephen M., Stewart, Richard C.
School: University of Maryland, College Park
Department: Cell Biology & Molecular Genetics
School Location: United States -- Maryland
Source: DAI-B 73/12(E), Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Bioinformatics
Keywords: Frameshifting, Ribosomes, mRNAs
Publication Number: 3517637
ISBN: 978-1-267-48052-1
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