Genetic analysis of Vprbp in mice Public Deposited

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Last Modified
  • March 20, 2019
Creator
  • Jackson, Sarah C.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • Ubiquitin-mediated protein degradation is a critical mechanism for regulating many cellular functions. Substrate proteins are specified through the activity of an E3 ubiquitin ligase. Cullin proteins serve as scaffolds to assemble hundreds of distinct multi-subunit E3 ubiquitin ligase complexes. My research focused on CUL4-based complexes, which use linker protein DDB1 to bind one of approximately 100 putative substrate recruiting proteins. Specifically, I investigated HIV1 viral protein R binding protein (VprBP), a WD40 repeat-containing protein which binds to CUL4-DDB1 and is predicted to function as a substrate recognition subunit. Functional studies of VprBP remain limited; there are currently no known substrates for CUL4-DDB1-VprBP and Vprbp knockout mice are early embryonic lethal. In my work, I first tested a hypothesis that VprBP functions in epigenetic modification of histones and intriguingly observed a possible role in histone H4 ubiquitylation. My subsequent work focused on understanding the function and mechanism of Vprbp by analyzing conditional mouse embryonic fibroblasts (MEFs) and mice. I discovered that VprBP is required for MEF proliferation and paradoxically that high levels of VprBP protein are associated with quiescent cells. Finally, by crossing conditional Vprbp mice with transgenic Ubiquitin C promoter driven Cre-ERT2+ mice, I was able to temporally control Vprbp disruption in an unbiased manner to explore phenotypes beyond embryonic lethality This work uncovered a role for Vprbp in the proliferation and survival of lymphocytes in mice.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics."
Advisor
  • Xiong, Yue
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  • Chapel Hill, NC
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  • Open access
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