Ubiquitin and Ubiquitin-Like Proteins in Cell Cycle Regulation Public Deposited

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Last Modified
  • March 20, 2019
Creator
  • Mills, Christine
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Cell cycle is a tightly regulated process; however, it is mis-regulated in many cancers, leading to increased proliferation. Our lab is interested in better understanding cell cycle regulation, in particular, regulation by the ubiquitin system, which controls targeted protein degradation. The following work focuses on the modular ubiquitin E3 ligase composed of SKP1/CUL1/F-box protein (SCF) with its substrate adapter Cyclin F. Cyclin F is a unique F-box protein in that it is highly cell cycle regulated, and has been revealed as a key regulator of cell cycle progression despite few of its substrates having been identified. Our lab aims to identify novel Cyclin F substrates, and determine how these substrates regulate cell cycle processes. The Cyclin F substrate, Nucleolar and Spindle Associated Protein 1 (NUSAP1), is a microtubule binding protein implicated in mitotic spindle stability and chromosome segregation, however, how it functions is unknown. I have identified a novel interaction between NUSAP1 and a small ubiquitin-related modifier (SUMO) E3 ligase composed of Ran Binding Protein 2 (RanBP2), Ran GTPase Activating Protein 1 (RanGAP1) and the SUMO E2 conjugating enzyme, UBC9. This work provides evidence that NUSAP1 may function in the SUMO pathway to promote faithful chromosome segregation. Cell cycle and metabolic regulation are critical to the growth and proliferation of normal cells, and these systems can be rewired in cancer to promote proliferation. Better understanding how these processes are integrated could provide key insights into how cancers proliferate. The following work identifies Sirtuin 5, a mitochondrial deacylating enzyme, as a novel Cyclin F substrate. Sirtuin 5 is a known regulator of key metabolic processes including gluconeogenesis and urea production, among others. To date, identified Cyclin F substrates are all involved in significant cell cycle processes, however, Sirtuin 5 has never been connected to cell cycle. This data reveals a new role for Sirtuin 5 as a regulator of G1 progression and suggests a possible role in quiescence. Furthermore, this data provides a link between cell cycle progression and metabolism. Additional research is needed to understand what possible metabolites are involved in this regulation, and how it is mis-regulated in cancer.
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Advisor
  • Johnson, Gary
  • Cook, Jean
  • Emanuele, Michael
  • Graves, Lee
  • Bloom, Kerry
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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