Skip to content
Login Register

#APC/C-Cdh1

2 public questions tagged with this topic.

Cell Cycle Regulation

The APC/C-Cdh1 complex is required for:

Specificity and timing of APC/C activity arise from sequential association with two adaptors, Cdc20 and Cdh1, both containing seven WD40 repeats forming beta-propeller that binds D-box and KEN motifs. During prometaphase and metaphase, APC/C-Cdc20 polyubiquitinates securin and cyclin B to trigger anaphase and mitotic exit. At telophase, cyclin B degradation reduces CDK1 activity, allowing Cdc14 phosphatase to dephosphorylate Cdh1, enabling its binding to APC/C core. APC/C-Cdh1 then operates from late mitosis through entire G1, continuously ubiquitinating mitotic cyclins A and B, mitotic kinases Polo and Aurora, Geminin inhibitor of licensing, and even Cdc20 itself, ensuring low CDK environment. Low CDK permits pre-replication complex formation consisting of ORC, Cdc6, Cdt1, and double hexamer of MCM2-7 helicase loaded at origins. As cyclin E-CDK2 accumulates at G1/S, it phosphorylates Cdh1 creating 14-3-3 sites, displacing it from APC/C and inactivating ligase, allowing S-phase cyclin accumulation and transition to next cycle. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Peters, Nature Reviews Mol Cell Biol 2006, APC/C Mechanisms. Alberts 7th ed., Chapter 17.

View Details
Cell Cycle Regulation

The role of APC/C-Cdh1 in cell cycle regulation is to:

Mitotic exit and establishment of G1 phase require elimination of mitotic cyclins that maintain high CDK1 activity and inhibition of microtubule dynamics regulators. While APC/C activated by Cdc20 initiates anaphase by degrading securin and partially degrading cyclin B, a second wave driven by APC/C bound to Cdh1, also known as Hct1, completes program. APC/C-Cdh1 recognizes distinct destruction box and KEN box motifs in substrates including remaining Clb2 and Clb5 cyclins in yeast, cyclin A and cyclin B1 in mammals, polo-like kinase Plk1, Aurora kinases A and B, and Cdc20 itself, targeting them for proteasomal degradation during late mitosis and early G1. Degradation results in loss of CDK1 activity, allowing activation of phosphatases and reassembly of nuclear envelope, chromosome decondensation, and licensing of replication origins. APC/C-Cdh1 also stabilizes G1 by preventing premature S-phase entry. Phosphorylation of Cdh1 by CDKs in S and early M phases inhibits it, restricting activity to period of low CDK activity. Thus role of APC/C-Cdh1 is to promote mitotic exit by degrading mitotic cyclins and associated mitotic regulators, coordinating cytoskeletal remodeling with cell cycle reset.

Ref: Visintin et al., Genes Dev 1998, APC/C-Cdh1 in Mitotic Exit; Peters, Nature Rev Mol Cell Biol 2006, APC/C Regulation.

View Details