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Molecular and Cellular Biology, November 2006, p. 7977-7990, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00819-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

DDB1 Maintains Genome Integrity through Regulation of Cdt1{triangledown} ,{dagger}

Courtney A. Lovejoy,1 Kimberli Lock,2 Ashwini Yenamandra,2 and David Cortez1*

Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232,1 Genetics Associates, Inc., Nashville, Tennessee 372032

Received 8 May 2006/ Returned for modification 3 July 2006/ Accepted 22 August 2006

DDB1, a component of a Cul4A ubiquitin ligase complex, promotes nucleotide excision repair (NER) and regulates DNA replication. We have investigated the role of human DDB1 in maintaining genome stability. DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints. Depletion of Cul4A yields similar phenotypes, indicating that an E3 ligase function of DDB1 is important for genome maintenance. In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved. One substrate of DDB1-Cul4A that is crucial for preventing genome instability is Cdt1. DDB1-depleted cells exhibit increased levels of Cdt1 protein and rereplication, despite containing other Cdt1 regulatory mechanisms. The rereplication, accumulation of DNA damage, and activation of checkpoint responses in DDB1-depleted cells require entry into S phase and are partially, but not completely, suppressed by codepletion of Cdt1. Therefore, DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation.

* Corresponding author. Mailing address: Vanderbilt University, Department of Biochemistry, 613 Light Hall, Nashville, TN 37232. Phone: (615) 322-8547. Fax: (615) 343-0704. E-mail: David.Cortez{at}vanderbilt.edu.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 7977-7990, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00819-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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