A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1
Open accessAbstract
Cul4 E3 ubiquitin ligases contain the cullin 4 scaffold and the triple beta propeller Ddb1 adaptor protein, but few substrate receptors have been identified. Here, we identify 18 Ddb1- and Cul4-associated factors (DCAFs), including 14 containing WD40 repeats. DCAFs interact with multiple surfaces on Ddb1, and the interaction of WD40-containing DCAFs with Ddb1 requires a conserved "WDXR" motif. DCAF2/Cdt2, which is related to S. pombe Cdt2, functions in Xenopus egg extracts and human cells to destroy the replication licensing protein Cdt1 in S phase and after DNA damage. Depletion of human Cdt2 causes rereplication and checkpoint activation. In Xenopus, Cdt2 is recruited to replication forks via Cdt1 and PCNA, where Cdt1 ubiquitylation occurs. These studies uncover diverse substrate receptors for Cul4 and identify Cdt2 as a conserved component of the Cul4-Ddb1 E3 that is essential to destroy Cdt1 and ensure proper cell cycle regulation of DNA replication.
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GM01389 cells defective in DDB2 carry a DDB2 mutation that impairs complex formation with DDB1 and consequently the formation of a functional DDB-XPC complex.
“DDB2-defective GM01389 cells carry mutation in DDB2 [52], which affects complex formation with DDB1 [58], and consequently the formation of functional DDB-XPC complex.”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [58]
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“DDB2-defective GM01389 cells carry mutation in DDB2 [52], which affects complex formation with DDB1 [58], and consequently the formation of functional DDB-XPC complex.”
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- Authors
- Jin, J., Arias, E. E., Chen, J., Harper, J. W., & Walter, J. C.
- Affiliations
- Harvard University (US)
- Corresponding author
- Harper, J. Wade
- Walter, Johannes C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 23
- Issue
- 5
- Pages
- 709-721
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2068784898
- Cited by
- 632
- References
- 34
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 29 · 2023: 23 · 2022: 20 · 2021: 30 · 2020: 31 · 2019: 35 · 2018: 28 · 2017: 34 · 2016: 29 · 2015: 29 · 2014: 44 · 2013: 36 · 2012: 36
- FWCI
- 13.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG11085, R01AG011085)
- National Institute of General Medical Sciences (GM54137, R01GM054137)
- Topics
- 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
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Cdt2, Cdt1, DDB1, WD40 repeats, substrate receptor, S phase, DNA replication licensing, re-replication, DNA damage checkpoint, PCNA, replication fork, ubiquitination, cell cycle regulation
- MeSH terms
- Amino Acid Sequence, Animals, Chromatin, DNA Damage, DNA Replication, DNA-Binding Proteins, HeLa Cells, Humans, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Protein Processing, Post-Translational, Receptors, Cell Surface, Xenopus laevis, Reproducibility of Results, G2 Phase, S Phase, Cell Cycle Proteins, Amino Acid Motifs, Xenopus Proteins, Ubiquitin-Protein Ligases, Cullin Proteins, Adaptor Proteins, Signal Transducing
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