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    DNA Secondary Structures in the Promoters of Human VEGF and RET Genes and Their Roles in Gene Transcriptional Regulation

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    Author
    Guo, Kexiao
    Issue Date
    2008
    Keywords
    DNA secondary structures
    Drug targeting
    Promoter
    RET
    transcription factors
    VEGF
    Advisor
    Hurley, Laurence H.
    Committee Chair
    Hurley, Laurence H.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Unusual DNA secondary structures, especially G-quadruplexes and i-motifs, play important roles in gene transcriptional regulation and have been identified as novel drug targets. In this dissertation, I explored their formation in the human VEGF and RET promoters and their roles in gene transcriptional regulation. VEGF is a key regulator of angiogenesis and is up-regulated in many types of tumors. A poly-guanine/poly-cytosine (polyG/polyC) tract in its proximal promoter (-85 to -50 base pairs relative to the transcription starting site) is essential for both basal and inducible VEGF expression. I demonstrated that the guanine-rich (G-rich) and cytosine-rich (C-rich) strands in the VEGF proximal promoter are able to form G-quadruplex and i-motif structures, respectively. The major G-quadruplex formed by the VEGF G-rich sequence is an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:4:1 arrangement of three double-chain-reversal loops (two single-base loops and one loop with four bases). The complementary C-rich sequence in the same region forms an intramolecular i-motif containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration (two double-base loops and one loop with three bases). The Gquadruplexes formed by the native VEGF G-rich and its derivative sequences were also confirmed by NMR. In addition, various transcription factors including Sp1, hnRNP K, CNBP and nucleolin, which recognize different DNA structural elements including single-stranded, double-stranded or G-quadruplex/i-motif DNA in the VEGF proximal promoter, have been confirmed by EMSA, siRNA and chromatin immunoprecipitation (ChIP) assay, suggesting that the DNA in the VEGF proximal promoter region is capable of undergoing transitions between those three structures. Based on my studies, I have proposed a model to describe how various transcription factors recognize different DNA structures in the VEGF proximal promoter to regulate transcription. In the proximal promoter of another important oncogene RET, I demonstrated that the guanine-rich strand forms an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:3:1 arrangement of three double-chain-reversal loops. The complementary cytosine-rich strand forms an i-motif structure containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration. Moreover, G-quadruplex-interactive compounds TMPyP4 and telomestatin were shown to further stabilize the RET G-quadruplex structure.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Biochemistry
    Graduate College
    Degree Grantor
    University of Arizona
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