Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Mar-Apr;18(6-7):652-660.
doi: 10.1080/15384101.2019.1593646. Epub 2019 Mar 28.

Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

Thomas Bonacci  1 , Michael J Emanuele  1   2
Affiliations
Review

Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

Thomas Bonacci et al. Cell Cycle. 2019 Mar-Apr.

Abstract

The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase and a key regulator of cell cycle progression. By triggering the degradation of mitotic cyclins, APC/C controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Thus, the dynamic activities of both APC/C and CDK sit at the core of the cell cycle oscillator. The APC/C controls a large number of substrates and is regulated through multiple mechanisms, including cofactor-dependent activation. These cofactors, Cdc20 and Cdh1, recognize substrates, while the specific E2 enzymes UBE2C/UbcH10 and UBE2S cooperate with APC/C to build K11-linked ubiquitin chains on substrates to target them for proteasomal degradation. However, whether deubiquitinating enzymes (DUBs) can antagonize APC/C substrate ubiquitination during mitosis has remained largely unknown. We recently demonstrated that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C substrates. Cezanne binds APC/C substrates, reverses their ubiquitination and protects them from degradation. Accordingly, Cezanne depletion accelerates APC/C substrate degradation, leading to errors in mitotic progression and formation of micronuclei. Moreover, Cezanne is significantly amplified and overexpressed in breast cancers. This suggests a potential role for APC/C antagonism in the pathogenesis of disease. APC/C contributes to chromosome segregation fidelity in mitosis raising the possibility that copy-number and expression changes in Cezanne observed in cancer contribute to the etiology of disease. Collectively, these observations identify a new player in cell cycle progression, define mechanisms of tempered APC/C substrate destruction and highlight the importance of this regulation in maintaining chromosome stability.

Keywords: APC/C; Cezanne; Mitosis.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Cezanne is a DUB antagonizing APC/C ubiquitination and degradation. APC/C recognizes and interacts with a cell cycle substrate. Following recruitment of the APC/C specific, ubiquitin charged E2s, UB2C and UBE2S, the substrate gets ubiquitinated with a K11-linked ubiquitin chain. After dissociation from APC/C, the ubiquitinated substrate can be either degraded by the proteasome or deubiquitinated by Cezanne, which therefore contributes to the kinetics of substrate degradation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hartwell LH, Culotti J, Pringle JR, et al. Genetic control of the cell division cycle in yeast. Science. 1974;183:46–51. - PubMed
    1. Morgan DO. The cell cycle: principles of control. Sunderland (MA): New Science Press in association with Oxford University Press; 2007.
    1. Glotzer M, Murray AW, Kirschner MW.. Cyclin is degraded by the ubiquitin pathway. Nature. 1991;349:132–138. - PubMed
    1. Husnjak K, Dikic I. Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem [Internet] 2012;81:291–322. - PubMed
    1. Hershko A, Ciechanover A, Varshavsky A. The ubiquitin system. Nat Med. 2000;6:1073–1081. - PubMed

Publication types

MeSH terms