Reverse the curse--the role of deubiquitination in cell cycle control

Abstract

Reversible protein ubiquitination is a crucial mechanism regulating the progression through the eukaryotic cell cycle. Ubiquitin-dependent signaling is terminated by specific deubiquitinating enzymes (DUBs), which now are known to be integral components of the core cell cycle machinery and cell cycle checkpoints. The importance of DUBs for cell cycle control is underscored by their frequent misregulation in cancer. Here, we discuss the role of deubiquitinating enzymes in controlling proliferation.

Figure 1

Usp1 as an example for multi-layered DUB regulation. Usp1 expression is regulated in a cell cycle-dependent manner, but newly synthesized, monomeric Usp1 has low activity. Oligomerization with a WD40-repeat containing binding partner, UAF1, stimulates the DUB-activity of Usp1. Usp1, however, can initiate its inactivation by catalyzing the cleavage of its own catalytic domain. Dissociation from UAF1 will complete Usp1 inactivation and potentially trigger its proteasomal degradation.

Figure 2

Usp44 as an example of DUB-dependent cell cycle control. When the spindle checkpoint is active, the ubiquitin ligase APC/C is inhibited by binding of Mad2 to the substrate-targeting factor Cdc20. Following the completion of chromosome attachment, the p31comet protein is activated and allows APC/C and UbcH10 to catalyze multiubiquitination of Cdc20. The APC/C-dependent multiubiquitination triggers dissociation of the Mad2 inhibitor and full activation of the APC/C. Premature activation of the APC/C is inhibited by the Usp44 deubiquitinating enzyme. Usp44 is activated in mitosis, which potentially requires its mitotic phosphorylation or recruitment of binding partners. Inhibition of CDK-activity, which is caused by the APC/C-dependent degradation of cyclins, leads to degradation of Usp44. Thus, Usp44 both regulates the APC/C and is regulated, albeit indirectly, by the APC/C.