- Cdh1 (also known as FZR1) is a key activator of the anaphase‑promoting complex/cyclosome (APC/C), one of the most important ubiquitin ligases in eukaryotic cell‑cycle control. Whereas Cdc20 drives APC/C activity during metaphase and anaphase, Cdh1 functions later in mitosis and throughout G1, ensuring that cells exit mitosis correctly, maintain genomic stability and prepare for the next cell‑cycle round. Cdh1’s ability to target mitotic cyclins and other regulatory proteins for degradation makes it a central guardian of the G1 phase and a critical determinant of whether cells commit to proliferation or remain quiescent.
- Cdh1 becomes active after the metaphase‑to‑anaphase transition, when CDK1 activity declines. High CDK1 levels inhibit Cdh1 through phosphorylation, but once Cyclin B is degraded, Cdh1 is dephosphorylated and binds to APC/C. This shift marks a major transition: APC/C–Cdh1 clears mitotic regulators such as Cyclin A, Cyclin B, Aurora A, Plk1, and Geminin, ensuring that cells do not re‑enter mitosis prematurely. By maintaining low CDK activity, Cdh1 stabilises the G1 phase and prevents unscheduled S‑phase entry. This regulatory logic ensures that the cell cycle proceeds in a unidirectional manner.
- Cdh1 also plays a major role in replication licensing. By targeting Geminin for degradation, APC/C–Cdh1 allows Cdt1 and the MCM complex to assemble at replication origins. This ensures that DNA replication can occur only once per cycle. Without Cdh1, Geminin persists, replication origins remain blocked, and cells may enter S phase with incomplete licensing, leading to replication stress and genomic instability.
- In addition to its canonical role in G1, Cdh1 is essential for maintaining cell‑cycle exit in differentiated or quiescent cells. Neurons, muscle cells and other post‑mitotic tissues rely on sustained APC/C–Cdh1 activity to suppress mitotic gene expression. Cdh1 also contributes to endoreduplication, where repeated S phases occur without mitosis. In plants and some animal tissues, APC/C–Cdh1 helps maintain low mitotic CDK activity, enabling cells to undergo successive rounds of DNA replication without division.
- Cdh1 is tightly regulated by multiple mechanisms. CDK‑dependent phosphorylation prevents premature activation, while the inhibitor Emi1 blocks APC/C–Cdh1 during S and G2 phases. Ubiquitin‑mediated turnover of Cdh1 itself provides an additional layer of control. These regulatory systems ensure that Cdh1 acts only when cells must exit mitosis or maintain G1 stability.
- Cdh1 has significant implications in cancer biology. Loss or reduction of Cdh1 activity leads to accumulation of mitotic cyclins, unscheduled S‑phase entry, replication stress and chromosomal instability—hallmarks of tumour development. Conversely, some cancers show aberrant Cdh1 activity that supports survival under stress. Because APC/C–Cdh1 controls many oncogenic regulators, it is being explored as a therapeutic target. Modulating Cdh1 activity may help restore proper cell‑cycle control in tumour cells or sensitise them to chemotherapy.
- In summary, Cdh1 is a master regulator of mitotic exit, G1 maintenance and replication licensing. By activating APC/C at the correct time, Cdh1 ensures that cells degrade mitotic regulators, maintain genomic stability and commit to either proliferation or differentiation. Its precise regulation is essential for healthy cell‑cycle progression, and its dysregulation contributes to cancer and other proliferative disorders.
