CENP-W inhibits CDC25A degradation by destabilizing the SCF^β-TrCP-1 complex at G₂/M

Skp, Cullin, F-box (SCF)^β-TrCP-1 ubiquitin ligases play a central role in cell cycle regulation and tumorigenesis via proteolytic cleavage of many essential cell cycle regulators. In this study, we propose that centromere protein (CENP)-W, a newly identified kinetochore component, is a novel negative regulator of the SCF^β-TrCP-1 complex. CENP-W interacts with Cullin (CUL)-1 and β-Transducin repeat-containing protein (β-TrCP)-1 through highly overlapped binding sites with S-phase kinase-associated protein (SKP)-1. CENP-W is incorporated into the SCF^β-TrCP-1 complex to promote complex disassembly. Unlike other known regulators that increase SCF^β-TrCP-1 ubiquitin ligase activity by promoting complex reassociation, CENP-W-mediated complex disorganization induced β-TrCP1 degradation and consequently decreased its activity. The association between CENP-W and the SCF^β-TrCP-1 complex was prominent during the G₂/M transition in the nucleus. Especially, CENP-W knockdown decreased the cell division cycle-25A protein level, leading to a delay in mitotic progression. We propose that CENP-W participates in cell cycle regulation by modulating SCF^β-TrCP-1 ubiquitin ligase activity.-Cheon, Y., Lee, S. CENP-W inhibits CDC25A degradation by destabilizing the SCF^β-TrCP-1 complex at G₂/M.