Cited by 632Ubiquitin and proteasome pathwaysDNA Repair MechanismsCancer-related Molecular Pathways

A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1

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Jin, Jianping, Arias, Emily E., Chen, Jing, Harper, J. Wade, Walter, Johannes C.·2006·Molecular Cell

Abstract

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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Crossref · 10.1016/j.molcel.2006.08.010

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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
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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