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.
|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|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be