CDC6

Cdc6, or cell division cycle 6 homolog, is a conserved eukaryotic protein that functions as a key component of the DNA replication licensing machinery. It participates in the origin recognition complex–Cdc6–Cdt1–MCM2-7 licensing pathway that marks replication origins during G1. Working with the origin recognition complex, Cdc6 helps recruit the MCM2-7 helicase complex to chromosomal origins, enabling the formation of the pre-replicative complex (pre-RC). Once licensed, origins are held in a ready state to initiate DNA synthesis when S phase begins.

Cdc6 is part of the AAA+ ATPase family and binds ATP; ATP binding and hydrolysis by Cdc6 contribute to loading of the MCM2-7 helicase onto DNA and the assembly of the pre-RC. The licensed origins are then activated later in the cell cycle by S-phase kinases to unwind DNA and start replication.

Regulation of Cdc6 is tight and multi-layered. Its expression and nuclear localization are highest in late M and early G1, declining as cells progress through S phase. Phosphorylation by cyclin-dependent kinases promotes ubiquitin-mediated degradation, limiting Cdc6 activity to G1. Cdc6 activity is further regulated indirectly by geminin, which inhibits Cdt1 to prevent re-licensing, thereby contributing to once-per-cell-cycle replication. In many organisms, Cdc6 stability is controlled by ubiquitin ligases such as SCF complexes and APC/C, ensuring timely turnover.

Cdc6 is essential for proper DNA replication in yeast and animals. Misregulation of licensing factors, including Cdc6, can lead to re-replication stress and genomic instability, a feature associated with oncogenesis. The protein is widely studied as part of the replication licensing apparatus and as a potential target for understanding and treating replication-associated diseases.