PUBLICATION
DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint
- Authors
- Sansam, C.L., Shepard, J.L., Lai, K., Ianari, A., Danielian, P.S., Amsterdam, A., Hopkins, N., and Lees, J.A.
- ID
- ZDB-PUB-061108-24
- Date
- 2006
- Source
- Genes & Development 20(22): 3117-3129 (Journal)
- Registered Authors
- Amsterdam, Adam, Hopkins, Nancy, Sansam, Chris, Shepard, Jennifer
- Keywords
- DNA damage, checkpoints, replication, DTL, CDT2, CUL4, CDT1, DCAFs
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Cell Cycle Proteins/metabolism*
- Cullin Proteins/metabolism
- DNA Damage
- DNA-Binding Proteins/metabolism
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/radiation effects
- G2 Phase/physiology*
- G2 Phase/radiation effects
- Genetic Testing
- HCT116 Cells
- HeLa Cells
- Humans
- Mitosis/physiology*
- Mitosis/radiation effects
- Models, Biological
- Mutagenesis, Insertional
- Mutation/genetics
- Nuclear Proteins
- Protein Binding/radiation effects
- Radiation, Ionizing
- Ubiquitin-Protein Ligases/metabolism
- Zebrafish/embryology
- Zebrafish/metabolism*
- Zebrafish Proteins/metabolism*
- PubMed
- 17085480 Full text @ Genes & Dev.
Citation
Sansam, C.L., Shepard, J.L., Lai, K., Ianari, A., Danielian, P.S., Amsterdam, A., Hopkins, N., and Lees, J.A. (2006) DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes & Development. 20(22):3117-3129.
Abstract
Checkpoint genes maintain genomic stability by arresting cells after DNA damage. Many of these genes also control cell cycle events in unperturbed cells. By conducting a screen for checkpoint genes in zebrafish, we found that dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint. We subsequently found that dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication. Both the checkpoint and replication roles are conserved in human DTL. Our data indicate that the rereplication reflects a requirement for DTL in regulating CDT1, a protein required for prereplication complex formation. CDT1 is degraded in S phase to prevent rereplication, and following DNA damage to prevent origin firing. We show that DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation in unperturbed cells and following DNA damage. The cell cycle defects of Dtl-deficient zebrafish are suppressed by reducing Cdt1 levels. In contrast, the early G2/M checkpoint defect appears to be Cdt1-independent. Thus, DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping