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      L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes.

      Cell Cycle

      Adaptor Proteins, Signal Transducing, deficiency, metabolism, Animals, Carrier Proteins, Cullin Proteins, isolation & purification, DNA-Binding Proteins, Gamma Rays, HeLa Cells, Heat-Shock Proteins, Humans, Mice, Nuclear Proteins, Polyubiquitin, Proliferating Cell Nuclear Antigen, Protein Binding, radiation effects, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-mdm2, Thermodynamics, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ultraviolet Rays

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          The CUL4-ROC1 E3 ligase complex regulates genome stability, replication and cell cycle progression. A novel WD40 domain-containing protein, L2DTL/CDT2 and PCNA were identified as proteins associated with CUL4/DDB1 complexes. Inactivation of CUL4A, L2DTL, PCNA, DDB1 or ROC1 induced p53 stabilization and growth arrest. L2DTL, PCNA and DDB1/CUL4A complexes were found to physically interact with p53 tumor suppressor and its regulator MDM2/HDM2. The isolated CUL4A complexes display potent and robust polyubiquitination activity towards p53 and this activity is dependent on L2DTL, PCNA, DDB1, ROC1 and MDM2/HDM2. We also found that the interaction between p53 and CUL4 complex is regulated by DNA damage. Our data further showed that MDM2/HDM2 is rapidly proteolyzed in response to UV irradiation and this process is regulated by CUL4/DDB1 and PCNA. Our studies demonstrate that PCNA, L2DTL and the DDB1-CUL4A complex play critical and differential roles in regulating the protein stability of p53 and MDM2/HDM2 in unstressed and stressed cells.

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