L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes
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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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L2DTL interacts with PCNA and CUL4/DDB1 E3 ligase complexes.
“A human homologue of Drosophila lethal (2) denticleless protein, (L2DTL) was identified by mass spectrometry as a protein found to interact with proliferating cell nuclear antigen (PCNA) and cullin 4/DNA damage binding protein 1 (CUL4/DDB1) E3 ligase complexes [40].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [40]
UV damage induces CUL4/DDB1 and PCNA, leading to Mdm2 proteolysis.
“Data revealed UV damage induced CUL4/DDB1 and PCNA leading to Mdm2 proteolysis.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [40]
The L2DTL/PCNA/CUL4/DDB1 complex regulates p53 polyubiquitination through Mdm2, and individual components interact with both proteins.
“This multimeric protein complex regulated p53 polyubiquitination through Mdm2 and individual components were found to interact with both proteins.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [40]
CUL4/DDB1 along with PCNA caused Mdm2 levels to be decreased in response to UV treatment.
“It should also be pointed out as discussed in the homologous recombination section, that CUL4/DDB1 along with PCNA caused Mdm2 levels to be decreased in response to UV treatment [40].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [40]
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- Authors
- Banks, D., Wu, M., Higa, L. A., Gavrilova, N., Quan, J., Ye, T., Kobayashi, R., Sun, H., & Zhang, H.
- Affiliations
- Yale University (US)
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2006-07-06
- Volume
- 5
- Issue
- 15
- Pages
- 1719-1729
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2029620675
- Cited by
- 127
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 11
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion)
- Funders
- National Institutes of Health (5r01ca072878-05)
- National Cancer Institute (R01CA077695, CA-72878, CA98955, R01CA098955, CA77695)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- PCNA, p53, protein stability, DNA damage response, WD40 domain proteins, genome stability, cell cycle regulation
- MeSH terms
- Animals, Carrier Proteins, DNA-Binding Proteins, Gamma Rays, Heat-Shock Proteins, HeLa Cells, Humans, Nuclear Proteins, Protein Binding, Protein Processing, Post-Translational, Thermodynamics, Ultraviolet Rays, Tumor Suppressor Protein p53, Proliferating Cell Nuclear Antigen, Polyubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Cullin Proteins, Adaptor Proteins, Signal Transducing, Mice, Proto-Oncogene Proteins c-mdm2
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