Simplified model of cullin-based ubiquitin ligases. Mammals possess 7 cullins (Cul1, 2, 3, 4A, 4B, 5, and 7) that each form a scaffold allowing substrate-specificity modules to connect to domains with ubiquitin ligase activity. Target proteins (green) are either modified by a chain containing multiple ubiquitin molecules (red)—a prerequisite for degradation by the proteasome—or they are monoubiquitinated. Each cullin uses a certain type of recognition module for substrate binding. Cul4A uses specificity modules that contain DWD domains, of which there are up to 90 in humans, to target a diverse set of proteins for ubiquitination. Substrates of Cul4A include Cdt1 and p27, both involved in cell-cycle regulation, and the histones H2A, H3, and H4.²