ZFIN ID: ZDB-PUB-061108-24
DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint
Sansam, C.L., Shepard, J.L., Lai, K., Ianari, A., Danielian, P.S., Amsterdam, A., Hopkins, N., and Lees, J.A.
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.
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.