This project was concerned with the functional components of mammalian DNA replication origins and how the misuse of a start site for DNA replication at the FMR1 locus might contribute to human Fragile X Syndrome.
In the first part of this dissertation, I identified a novel origin of DNA replication near the CGG repeats at the human Fragile X Mental Retardation (FMR1) gene promoter. Expansion of these repeats leads to the epigenetic chromosome modifications that cause Fragile X Syndrome. The experiments described in this dissertation suggest that the position of the FMR1 origin favors contraction of the CGG repeats, thus providing a mechanism to avoid repeat expansion. This model predicts that a change in origin usage accompanies repeat expansion, and I discussed how this could occur.
In the second part of this dissertation, I examined the requirement of DNA sequence elements in a mammalian origin to direct DNA replication to start at specific chromosomal sites. In particular, I studied the role of a dinucleotide repeat (DNR) sequence element in the activity of the Chinese hamster dihydrofolate reductase origin beta. The DNR element could be functionally replaced with two different transcriptional elements. This result suggests that DNR shares a functional role with these elements, and we speculate that this role may be to create the proper chromatin environment for recruitment and action of other replication factors to initiate replication.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08242006-145518 |
| Date | 06 October 2006 |
| Creators | Gray, Steven James |
| Contributors | Terrence Dermody, James Patton, Katherine Friedman, Wallace Lestourgeon, Ellen Fanning |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08242006-145518/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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