• Login
    View Item 
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UA Campus RepositoryCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournalThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournal

    My Account

    LoginRegister

    About

    AboutUA Faculty PublicationsUA DissertationsUA Master's ThesesUA Honors ThesesUA PressUA YearbooksUA CatalogsUA Libraries

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Effect of Partial Poly (ADP-ribose) Glycohydrolase Gene Deletion on Cellular Responses to Genotoxic Stress

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    azu_etd_1848_sip1_m.pdf
    Size:
    2.751Mb
    Format:
    PDF
    Description:
    azu_etd_1848_sip1_m.pdf
    Download
    Author
    Gao, Hong
    Issue Date
    2006
    Keywords
    poly(ADP-ribose) glycohydrolase
    poly(ADP-ribose)
    poly(ADP-ribose) polymerase
    MNNG
    genotoxic stress
    NAD
    Advisor
    Jacobson, Myron K.
    Committee Chair
    Jacobson, Myron K.
    
    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
    Polymers of ADP-ribose (PAR) are rapidly synthesized by poly(ADPribose) polymerases (PARPs) and rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG) following genotoxic stress. Since PAR metabolism plays an important role in cell fate determination following genotoxic stress, enzymes involved in PAR metabolism potentially represent promising therapeutic targets for modulating diseases of inappropriate cell proliferation or death. PARP-1 has been well validated and several PARP-1 inhibitors are currently being evaluated in clinical trials for cancer and ischemia treatment. In contrast, the biological function of PARG is still poorly understood. Due to low abundance of protein levels in mammalian cells and its unique substrate, PARG potentially represents another attractive target for pathological conditions mentioned above. PARG-Δ2,3 cells derived from homozygous PARG-Δ2,3 mice with targeted disruption of exons 2 and 3 of the PARG gene are used in this dissertation. The nuclear isoform PARG60 in PARG-Δ2,3 cells lacks the putative regulatory domain A compared to the nuclear isoform PARG110 in wild type cells. We report in this dissertation that PARG-Δ2,3 cells accumulate less PAR in spite of more rapid depletion of NAD following treatment with N-methyl- N’- Nitro-N-Nitrosoguanidine (MNNG). The estimation of PARP and PARG activity in intact cells shows increased activity of both enzymes in PARG-Δ2,3 cells following MNNG treatment, indicating the important role of domain A in the regulation of PARG and PARP activity under these conditions. Following MNNG treatment, PARG-Δ2,3 cells show reduced formation of XRCC1 foci, decreased H2AX phosphorylation, decreased DNA break intermediates during repair, and increased cell death. The altered PAR metabolism and defective cellular responses related to DNA repair in PARG-Δ2,3 cells may contribute to increased sensitivity of these cells to MNNG. Studies presented in this dissertation clearly demonstrate the important role of PARG110 in PAR metabolism and cellular responses to genotoxic stress, and thus provide supportive data for the validation of PARG as a promising potential therapeutic target.
    Type
    text
    Electronic Dissertation
    Degree Name
    PhD
    Degree Level
    doctoral
    Degree Program
    Pharmaceutical Sciences
    Graduate College
    Degree Grantor
    University of Arizona
    Collections
    Dissertations

    entitlement

     
    The University of Arizona Libraries | 1510 E. University Blvd. | Tucson, AZ 85721-0055
    Tel 520-621-6442 | repository@u.library.arizona.edu
    DSpace software copyright © 2002-2017  DuraSpace
    Quick Guide | Contact Us | Send Feedback
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.