Abstract
Recent investigation of Cullin 4 (CUL4) has ushered this class of multiprotein ubiquitin E3 ligases to center stage as critical regulators of diverse processes including cell cycle regulation, developmental patterning, DNA replication, DNA damage and repair, and epigenetic control of gene expression. CUL4 associates with DNA Damage Binding protein 1 (DDB1) to assemble an ubiquitin E3 ligase that targets protein substrates for ubiquitin-dependent proteolysis. CUL4 ligase activity is also regulated by the covalent attachment of the ubiquitin-like protein NEDD8 to CUL4, or neddylation, and the COP9 signalosome complex (CSN) that removes this important modification. Recently, multiple WD40-repeat proteins (WDR) were found to interact with DDB1 and serve as the substrate-recognition subunits of the CUL4-DDB1 ubiquitin ligase. As more than 150–300 WDR proteins exist in the human genome, these findings impact a wide array of biological processes through CUL4 ligase-mediated proteolysis. Here, we review the recent progress in understanding the mechanism of CUL4 ubiquitin E3 ligase and discuss the architecture of CUL4-assembled E3 ubiquitin ligase complexes by comparison to CUL1-based E3s (SCF). Then, we will review several examples to highlight the critical roles of CUL4 ubiquitin ligase in genome stability, cell cycle regulation, and histone lysine methylation. Together, these studies provide insights into the mechanism of this novel ubiquitin ligase in the regulation of important biological processes.
Highlights
Ubiquitin-mediated proteolysis has been established as a key regulatory mechanism governing almost every biological process in the eukaryotic cell
Cullin 4 (CUL4) is a member of the cullin family of proteins, which share substantial homology to CUL1 originally identified in Caernorhabditis elegans [1]
These observations, together with the observation that human CUL4 [17] and DNA Damage Binding protein 1 (DDB1) [15,16,18] associated with multiple WDR proteins, and the demonstration that each WDR protein performs an unique CUL4-DDB1-dependent function [17,18] led to the establishment of WD40-repeat proteins as substrate-targeting subunits of CUL4-DDB1 ubiquitin E3 ligases
Summary
Ubiquitin-mediated proteolysis has been established as a key regulatory mechanism governing almost every biological process in the eukaryotic cell. The S. pombe CDT2 was independently identified as CSN2-associated protein that binds to Pcu4 [29] These observations, together with the observation that human CUL4 [17] and DDB1 [15,16,18] associated with multiple WDR proteins, and the demonstration that each WDR protein performs an unique CUL4-DDB1-dependent function [17,18] led to the establishment of WD40-repeat proteins as substrate-targeting subunits of CUL4-DDB1 ubiquitin E3 ligases. Maintenance of CDT1 destruction after DNA damage in WDR5-deficient cells and maintenance of H3K4 methylation in CDT2-silenced cells established that WDR proteins are substrate-targeting subunits of CUL4-DDB1 ubiquitin ligases. It will be interesting to analyze the contribution of E2 specificity to the processivity of CUL4 ubiquitination, since the association of the Polycomb PRC1 E3 ligase with different UbcH5 E2 isoforms has been shown to influence H2A ubiquitination [70]
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