Description
- Abstract:
- In eukaryotic cells, informational recoding and RNA interference (RNAi) proceed through structurally diverse double-stranded (ds) RNA molecules. Informational recoding of RNA by the catalytic deamination of adenosine to inosine ensues through the action of ADAR, an RNA editing enzyme. In Drosophila, many mRNAs involved in neuro-transmission serve as site-specific substrates for ADARs via base pairing interactions that generate short imperfect duplexes. However, long double strand RNA molecules exhibiting perfect complementarity can be modified extensively by promiscuous ADAR activity antagonizing RNAi-mediated gene silencing. dADAR also edits its own transcript, but the consequences of this auto-regulation regarding mRNA recoding and RNAi in vivo are not well understood. Using ends-out homologous recombination to bi-directionally interfere with dADAR regulation, I show that auto-editing of dAdar mRNA dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. In addition, I demonstrate that modifying dAdar auto-regulation affects adaptive complex behaviors. Furthermore, I demonstrate that dADAR can act as an enhancer or suppressor of position effect variegation (PEV) and this action can be bi-directionally modulated via its auto-regulation that alters a single amino acid. Together, these results reveal the in vivo relevance of homeostatic control over post-transcriptional mRNA re-coding events, as well as ADAR�s role in determining long dsRNA fate, a key regulator of heterochromatin formation. The research here highlights a more global function for RNA editing regarding neuronal transcriptomic regulation and emphasizes its pivotal role in organismal fitness.
- Notes:
- Thesis (Ph.D. -- Brown University (2011)
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Citation
Savva, Yiannis A.,
"Biological Consequences of Specific and Promiscuous A-to-I RNA Editing Revealed Through Precise Genetic Engineering."
(2011).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z07S7M1Q
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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations
Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department....