Cdc6

Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae (). It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea. CDC6 is an ATP binding protein and a member of the pre-replicative complex (pre-RC) together with the origin recognition complex (ORC), Cdt1 and the MCM complex (containing MCM2-7p). CDC6 assembles after ORC in an ATP dependent manner and is required for loading MCM proteins onto the DNA. Reconstruction of electron microscope images showed that the ORC-CDC6 complex forms a ring-shaped structure with similar dimensions to those of ring-shaped MCM helicase. A near-atomic resolution model of the entire ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) complex with DNA was assembled from EM data in 2017. It is thought that the CDC6-Cdt1 complex uses ATP hydrolysis to thread DNA through the central hole of the MCM doughnut. Mutations in the binding motif of CDC6 strongly suggest that ATP binding and hydrolysis is essential for its function. The minimal requirement for DNA binding has been mapped within its 47-amino acid sequence. Furthermore, Cdc6 indirectly inhibits activation of the p34cdc2/CDC28 M phase kinase, thus nuclear division is suppressed. CDC6 is normally present at high levels during the G1 phase of the cell cycle. This is partly because the CDC6 gene is only transcribed during G1 phase. On the onset of the S phase, CDC6 gets phosphorylated by the Cdc28-Clb5-Clb6 complex (Cdk2) and consequently becoming inactivated. This has been shown by introducing mutations in CDC6 at the consensus sites for Cdk2 phosphorylation (near the N-terminus) which inhibit degradation.