Switching DCAFs: Beyond substrate receptors.

Deciphering how DCAFs (DDB1-CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin-Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery ("catalytic DCAFs"). However, recent studies have suggested that some DCAFs might play a different role by targeting CRL4 complexes to distinct cellular compartments ("structural DCAFs"). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate-specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time.