|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.
|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|
|PubMed:||17085480 Full text @ Genes & Dev.|
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.
ABSTRACTCheckpoint 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.