Cdc6Cdt1

Cdc6 and Cdt1 are conserved eukaryotic proteins that function as replication licensing factors. Working with the Origin Recognition Complex (ORC), they are essential for assembling the pre-replicative complex at origins of replication during late mitosis and G1, thereby licensing origins for replication in the upcoming S phase.

Mechanism: ORC binds origin DNA; Cdc6 is recruited to ORC and, with ATP hydrolysis, promotes the loading of the MCM2-7 helicase complex onto DNA. Cdt1 binds MCM2-7 and delivers it to the ORC–Cdc6 complex to complete the loading, producing a double hexamer encircling DNA. This origin licensing step prepares origins for activation in S phase. Licensing is restricted to G1 when CDK activity is low, and remains stable until S phase begins.

Regulation: To prevent rereplication, Cdc6 and Cdt1 are regulated by multiple mechanisms. CDK-mediated phosphorylation promotes their degradation or inactivation; the inhibitor protein geminin binds Cdt1 during S and G2 to block re-loading; ubiquitin ligases such as SCF and CUL4-DDB1-based complexes contribute to Cdt1 turnover; Cdc6 is similarly controlled by degradation and localization changes. These controls ensure that licensing occurs once per cell cycle.

Significance: Proper Cdc6–Cdt1 function is essential for genome stability. Dysregulation, including overexpression of Cdc6 or Cdt1, can lead to rereplication and genomic instability and has been observed in various cancers. As part of the replication licensing apparatus, they are studied in the context of cell cycle control and cancer biology.