Cell Cycle and Cell Growth Regulation by the CUL4-DDB1-ROC1 Ubiquitin Ligases Public Deposited

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  • March 20, 2019
  • Hu, Jian
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Timely and efficient destruction of proteins in the cell is critical for its normal function. The ubiquitin-proteasome system is the major pathway by which the cell targets proteins for degradation in a specific manner. Ubiquitination is a process in which ubiquitin is covalently conjugated to proteins via an enzymatic cascade composed of an E1 activating enzyme, an E2 conjugating enzyme and an E3 ubiquitin ligase. The cullins are a family of evolutionarily conserved proteins that assemble a large family of cullin-dependent E3 ligases (CDLs). A unique feature of CDLs is that the cullins, through a conserved N-terminal domain interact with a specificity factor - either directly or through an adaptor - to recruit specific substrates. This dissertation is directed toward understanding the mechanism by which CUL4 targets substrates. I show here that CUL4 utilizes an adaptor DDB1 (damaged DNA binding protein 1) and the specificity factor DWD (DDB1 binding and WD40 repeat) proteins to target various substrates. Specifically, a DNA pre-replicative licensing factor CDT1 is ubiquitinated and degraded by CUL4-DDB1-CDT2 ubiquitin ligase in response to DNA damage, thereby constituting a novel cell cycle G1-S checkpoint. Although the mechanistic role is not known, PCNA (proliferating cell nuclear antigen) is required for the ubiquitination of CDT1 catalyzed by CUL4-DDB1-CDT2. TSC2 (Tuberous Sclerosis complex) is an important tumor suppressor which plays an essential role inhibiting cell growth. The majority of disease-associated mutations targeting TSC2 results in a substantial decrease in protein level, suggesting that protein turnover plays a critical role in TSC regulation. In this study, I present the evidence indicating that CUL4-DDB1-FBW5 is an E3 ubiquitin ligase regulating TSC2 protein stability.
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  • Xiong, Yue
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