Letter abstract
Nature Cell Biology 6, 1003 - 1009 (2004)
Published online: 26 September 2004 | doi:10.1038/ncb1172
Targeted ubiquitination of CDT1 by the DDB1–CUL4A–ROC1 ligase in response to DNA damage
Jian Hu1, Chad M. McCall1, Tomohiko Ohta1,2 & Yue Xiong1
Cullins assemble a potentially large number of ubiquitin ligases by binding to the RING protein ROC1 to catalyse polyubiquitination, as well as binding to various specificity factors to recruit substrates1, 2, 3, 4. The Cul4A gene is amplified in human breast and liver cancers, and loss-of-function of Cul4 results in the accumulation of the replication licensing factor CDT1 in Caenorhabditis elegans embryos and ultraviolet (UV)-irradiated human cells. Here, we report that human UV-damaged DNA-binding protein DDB1 associates stoichiometrically with CUL4A in vivo, and binds to an amino-terminal region in CUL4A in a manner analogous to SKP1, SOCS and BTB binding to CUL1, CUL2 and CUL3, respectively. As with SKP1–CUL1, the DDB1–CUL4A association is negatively regulated by the cullin-associated and neddylation-dissociated protein, CAND1. Recombinant DDB1 and CDT1 bind directly to each other in vitro, and ectopically expressed DDB1 bridges CDT1 to CUL4A in vivo. Silencing DDB1 prevented UV-induced rapid CDT1 degradation in vivo and CUL4A-mediated CDT1 ubiquitination in vitro. We suggest that DDB1 targets CDT1 for ubiquitination by a CUL4A-dependent ubiquitin ligase, CDL4ADDB1, in response to UV irradiation.
- Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.
- Present address: Division of Breast and Endocrine Surgery, St Marianna University School of Medicine, Kawasaki 216-8511, Japan.
Correspondence to: Yue Xiong1 e-mail: yxiong@email.unc.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
BTB proteins as henchmen of Cul3-based ubiquitin ligasesNature Cell Biology News and Views (01 Nov 2003)
Targeting protein ubiquitylation: DDB1 takes its RING offNature Cell Biology News and Views (01 Apr 2009)
See all 3 matches for News And ViewsRESEARCH
Molecular architecture and assembly of the DDB1?CUL4A ubiquitin ligase machineryNature Letters to Editor (05 Oct 2006)
A longevity protein, Lag2, interacts with SCF complex and regulates SCF functionThe EMBO Journal Article (04 Nov 2009)
See all 66 matches for Research
