Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

The anaphase‐promoting complex/cyclosome ( APC /C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC /C promotes the degradation of mitotic cyclins, it controls cell cycle‐dependent oscillations in cyclin‐dependent kinase ( CDK ) activity. Both CDK s and APC /C control a large number of substrates and are regulated by analogous mechanisms, including cofactor‐dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK , it remains largely unknown whether deubiquitinating enzymes ( DUB s) antagonize APC /C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/ OTUD 7B is a cell cycle‐regulated DUB that opposes the ubiquitination of APC /C targets. Cezanne is remarkably specific for K11‐linked ubiquitin chains, which are formed by APC /C in mitosis. Accordingly, Cezanne binds established APC /C substrates and reverses their APC /C‐mediated ubiquitination. Cezanne depletion accelerates APC /C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC /C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation.