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Molecular and Cellular Biology, February 2007, p. 1394-1406, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.00736-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Caenorhabditis elegans Replication Licensing Factor CDT-1 Is Targeted for Degradation by the CUL-4/DDB-1 Complex{triangledown}

Youngjo Kim and Edward T. Kipreos*

Department of Cellular Biology, University of Georgia, Athens, Georgia 30602-2607

Received 27 April 2006/ Returned for modification 23 May 2006/ Accepted 27 November 2006

The replication of genomic DNA is strictly regulated to occur only once per cell cycle. This regulation centers on the temporal restriction of replication licensing factor activity. Two distinct ubiquitin ligase (E3) complexes, CUL4/DDB1 and SCFSkp2, have been reported to target the replication licensing factor Cdt1 for ubiquitin-mediated proteolysis. However, it is unclear to what extent these two distinct Cdt1 degradation pathways are conserved. Here, we show that Caenorhabditis elegans DDB-1 is required for the degradation of CDT-1 during S phase. DDB-1 interacts specifically with CUL-4 but not with other C. elegans cullins. A ddb-1 null mutant exhibits extensive DNA rereplication in postembryonic BLAST cells, similar to what is observed in cul-4(RNAi) larvae. DDB-1 physically associates with CDT-1, suggesting that CDT-1 is a direct substrate of the CUL-4/DDB-1 E3 complex. In contrast, a deletion mutant of the C. elegans Skp2 ortholog, skpt-1, appears overtly wild type with the exception of an impenetrant gonad migration defect. There is no appreciable role for SKPT-1 in the degradation of CDT-1 during S phase, even in a sensitized ddb-1 mutant background. We propose that the CUL-4/DDB-1 ubiquitin ligase is the principal E3 for regulating the extent of DNA replication in C. elegans.

* Corresponding author. Mailing address: Department of Cellular Biology, University of Georgia, 724 Biological Sciences Bldg., Athens, GA 30602-2607. Phone: (706) 542-3862. Fax: (706) 542-4271. E-mail: ekipreos{at}cb.uga.edu.

{triangledown} Published ahead of print on 4 December 2006.

Molecular and Cellular Biology, February 2007, p. 1394-1406, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.00736-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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