Human Cdt1 is a nuclear localizing replication initiation factor that is expressed only during the G1 and S phases of the cell cycle. In conjunction with Cdc18, Cdt1 is required to load the MCM protein Cdc21 onto chromatin at the end of mitosis which is necessary to initiate DNA replication. After S-phase onset, Cdt1 protein levels decrease and are barely detectable in cells in early S-phase or G2. However, Cdt1 mRNA is expressed in S-phase-arrested cells, and its levels do not change dramatically during the cell cycle, suggesting that proteolytic degradation rather than transcriptional controls ensure proper accumulation of Cdt1. Cdt1 can associate with the DNA replication inhibitor geminin, which is present in the S and G2 phases of the cell cycle. Inhibition of DNA replication by geminin in cell-free DNA replication extracts can be reversed by the addition of excess Cdt1. Geminin may be responsible for preventing inappropriate origin firing by targeting Cdt1.
