Letter abstract
Nature Cell Biology 8, 1277 - 1283 (2006)
Published online: 15 October 2006 | doi:10.1038/ncb1490
CUL4–DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation
Leigh Ann Higa1,5, Min Wu1,5, Tao Ye2,3, Ryuji Kobayashi4, Hong Sun1 & Hui Zhang1,2
The CUL4–DDB1–ROC1 ubiquitin E3 ligase regulates cell-cycle progression, replication and DNA damage response1, 2, 3, 4. However, the substrate-specific adaptors of this ligase remain uncharacterized. Here, we show that CUL4–DDB1 complexes interact with multiple WD40-repeat proteins (WDRs) including TLE1-3, WDR5, L2DTL (also known as CDT2) and the Polycomb-group protein EED (also known as ESC). WDR5 and EED are core components of histone methylation complexes that are essential for histone H3 methylation and epigenetic control at K4 or K9 and K27, respectively5, 6, 7, whereas L2DTL regulates CDT1 proteolysis after DNA damage through CUL4–DDB1 (ref. 8). We found that CUL4A–DDB1 interacts with H3 methylated mononucleosomes and peptides. Inactivation of either CUL4 or DDB1 impairs these histone modifications. However, loss of WDR5 specifically affects histone H3 methylation at K4 but not CDT1 degradation, whereas inactivation of L2DTL prevents CDT1 degradation but not histone methylation. Our studies suggest that CUL4–DDB1 ligases use WDR proteins as molecular adaptors for substrate recognition, and modulate multiple biological processes through ubiquitin-dependent proteolysis.
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
- Laboratory of Chemical Genomics, The Shenzhen Graduate School of Peking University, Shenzhen, 518055, China.
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
- Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
- These authors contributed equally to this work.
Correspondence to: Hui Zhang1,2 e-mail: hui.zhang@yale.edu
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