Cdt1

Cdt1, or chromatin licensing and DNA replication factor 1, is a eukaryotic protein that plays a central role in initiating DNA replication. Working with the origin recognition complex (ORC) and Cdc6, CDT1 helps load the MCM2-7 helicase onto replication origins during late mitosis and G1, establishing the pre-replication complex that licenses origins for firing in S phase. By licensing origins once per cell cycle, CDT1 helps ensure genome duplication proceeds with fidelity and prevents rereplication.

CDT1 is tightly regulated at multiple levels. Its expression is highest in G1 and declines as cells enter S phase. Post-translational control includes ubiquitin-mediated degradation: the CRL4^Cdt2 ubiquitin ligase targets CDT1 for proteolysis in a PCNA-dependent manner during S phase; geminin binds CDT1 in S/G2 to block licensing and prevent re-licensing. In some contexts, SCF^Skp2 can promote degradation in late G1/early S. CDK activity also modulates CDT1 stability and licensing competence. Subcellular localization and interaction with ORC and MCM2-7 further regulate activity.

Structure and conservation: CDT1 contains domains that mediate interactions with ORC and MCM2-7 and is conserved across eukaryotes. It has been studied in yeast, Xenopus, and human cells, where it is essential for origin licensing.

Clinical relevance: Deregulation or overexpression of CDT1 can lead to rereplication and DNA damage, contributing to genome instability and oncogenesis. Consequently, CDT1 is explored as a contributor to cancer biology and as a potential target to modulate replication stress.