SURVEILLANCE AND TARGETING OF ABERRANT TRANSCRIPTS IN CAENORHABDITIS ELEGANS Public Deposited

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  • March 19, 2019
Creator
  • Leopold, Luciana
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • An organism requires mechanisms with which to protect the fidelity and integrity of the genome, transcriptome, and proteome in order not only to remain healthy and alive, but also to pass on viable genetic material to its offspring. To this end, the cell is constantly surveying the transcripts being expressed. When aberrant transcripts are produced, whether they be from endogenous or exogenous sources, mechanisms are required in order to silence or eradicate such messages before they become toxic to the cell. Two such mechanisms are nonsense-mediated mRNA decay (NMD), which targets transcripts bearing a premature termination codon (PTC), and RNA-induced epigenetic silencing (RNAe), which silences foreign loci in the genome in a heritable, stable manner. We have identified targets that require unique kinds of silencing that utilize already established NMD or RNAe machinery, but represent deviations from the standard. For example, the unc-54(r293) transcript was previously thought to be silenced by standard NMD, however I have shown that unc-54(r293) does not contain the canonical target PTC, and instead has a more complex molecular target. I also show that the integral SMG-1 component of the NMD machinery interacts with this target in a manner that is distinct from that of traditional NMD, as illustrated by the novel smg-1(yp3) separation-of-function allele. In the next example, we show that permanent, stable transgene silencing like that generated by RNAe in a single generation, can be attained in certain transgenes only after several generations of successive crossing. These processes are molecularly similar, as they both require the Argonaute protein PRG-1. However, they differ in that single-generation RNAe silencing becomes independent of PRG-1 after initiation, whereas the silencing we observe in multigenerational RNAe requires PRG-1 in order to maintain its silent state.
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  • In Copyright
Advisor
  • Marzluff, William
  • Reiner, David
  • Ahmed, Shawn
  • Conlon, Frank
  • Bautch, Victoria
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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