Who guards the guardian? Mechanisms that restrain APC/C during the cell cycle

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1865; no. 12; pp. 1924 - 1933
• Main Authors: Kernan, Jennifer, Bonacci, Thomas, Emanuele, Michael J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2018
• Subjects: APC/C; Cell cycle; Deubiquitinating enzyme (DUB); Proteolysis; Ubiquitin; Ubiquitin ligase; Ubiquitin; APC/C; Deubiquitinating enzyme (DUB); Ubiquitin ligase; Proteolysis; Cell cycle
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2018.09.011

The cell cycle is principally controlled by Cyclin Dependent Kinases (CDKs), whose oscillating activities are determined by binding to Cyclin coactivators. Cyclins exhibit dynamic changes in abundance as cells pass through the cell cycle. The sequential, timed accumulation and degradation of Cyclins, as well as many other proteins, imposes order on the cell cycle and contributes to genome maintenance. The destruction of many cell cycle regulated proteins, including Cyclins A and B, is controlled by a large, multi-subunit E3 ubiquitin ligase termed the Anaphase Promoting Complex/Cyclosome (APC/C). APC/C activity is tightly regulated during the cell cycle. Its activation state increases dramatically in mid-mitosis and it remains active until the end of G1 phase. Following its mandatory inactivation at the G1/S boundary, APC/C activity remains low until the subsequent mitosis. Due to its role in guarding against the inappropriate or untimely accumulation of Cyclins, the APC/C is a core component of the cell cycle oscillator. In addition to the regulation of Cyclins, APC/C controls the degradation of many other substrates. Therefore, it is vital that the activity of APC/C itself be tightly guarded. The APC/C is most well studied for its role and regulation during mitosis. However, the APC/C also plays a similarly important and conserved role in the maintenance of G1 phase. Here we review the diverse mechanisms counteracting APC/C activity throughout the cell cycle and the importance of their coordinated actions on cell growth, proliferation, and disease. •The APC/C ubiquitin ligase is active in G1 phase, and guards against premature entry into S-phase.•Due to its vital role in cell cycle and genome stability, multiple mechanisms guard against inappropriate APC/C activation.•Other E3 ligases, deubiquitinases, kinases and transcription factors restrain APC/C activity during S, G2 and early mitosis.•Defective control of APC/C is likely important in cancers where the barrier to proliferation has been weakened