APCCCdh1

APC/C with co-activator CDH1, commonly written APC/C^CDH1, is a multi-subunit E3 ubiquitin ligase that functions in the ubiquitin-proteasome system to regulate the eukaryotic cell cycle. It is the form of the anaphase-promoting complex/cyclosome (APC/C) that operates predominantly from late mitosis through G1, targeting a set of regulatory proteins for degradation to ensure proper cell cycle progression and genomic stability.

The activity of APC/C^CDH1 is controlled by the phosphorylation state of CDH1. CDH1 is inactivated by CDK-dependent phosphorylation during S and G2, and becomes active when phosphatases remove these phosphate groups at mitotic exit. Once bound to the APC/C core, CDH1 directs substrate recognition via destruction motifs such as the D-box and KEN-box, leading to ubiquitination and subsequent proteasomal degradation of its targets. These substrates include mitotic regulators and DNA replication licensing factors, helping to prevent premature entry into S phase and to promote orderly mitotic exit and reset of the cell cycle.

APC/C^CDH1 functions in coordination with APC/C bound to Cdc20, which acts earlier in mitosis to drive the metaphase-to-anaphase transition. Together, the two forms of APC/C orchestrate successive cell cycle transitions and maintain cellular homeostasis. In addition to its fundamental role in cell biology, dysregulation of APC/C^CDH1 has been implicated in cancer and developmental disorders; germline mutations in CDH1 are associated with hereditary diffuse gastric cancer, and altered APC/C^CDH1 activity has been observed in various tumors. Ongoing research seeks to delineate its full substrate repertoire and therapeutic implications.