InterPro domain: IPR015163

The C-terminal domain of cell division control protein 6 (CDC6) assumes a winged helix fold, with a five alpha-helical bundle (alpha15-alpha19) structure, backed on one side by three beta strands (beta6-beta8). It has been shown that this domain acts as a DNA-localisation factor, however its exact function is, as yet, unknown. Putative functions include: (1) mediation of protein-protein interactions and (2) regulation of nucleotide binding and hydrolysis. Mutagenesis studies have shown that this domain is essential for appropriate CDC6 activity [ 1 ].

Cdc6 (also known as Cell division cycle 6 or Cdc18) functions as a regulator at the early stages of DNA replication, by helping to recruit and load the Minichromosome Maintenance Complex (MCM) onto DNA and may have additional roles in the control of mitotic entry. Precise duplication of chromosomal DNA is required for genomic stability during replication. Cdc6 has an essential role in DNA replication and irregular expression of Cdc6 may lead to genomic instability. Cdc6 over-expression is observed in many cancerous lesions. DNA replication begins when an origin recognition complex (ORC) binds to a replication origin site on the chromatin. Studies indicate that Cdc6 interacts with ORC through the Orc1 subunit, and that this association increases the specificity of the ORC-origins interaction. Further studies suggest that hydrolysis of Cdc6-bound ATP promotes the association of the replication licensing factor Cdt1 with origins through an interaction with Orc6 and this in turn promotes the loading of MCM2-7 helicase onto chromatin. The MCM2-7 complex promotes the unwinding of DNA origins, and the binding of additional factors to initiate the DNA replication. S-Cdk (S-phase cyclin and cyclin-dependent kinase complex) prevents rereplication by causing the Cdc6 protein to dissociate from ORC and prevents the Cdc6 and MCM proteins from reassembling at any origin. By phosphorylating Cdc6, S-Cdk also triggers Cdc6's ubiquitination. The Cdc6 protein is composed of three domains, an N-terminal AAA+ domain with Walker A and B, and Sensor-1 and -2 motifs. The central region contains a conserved nucleotide binding/ATPase domain and is a member of the ATPase superfamily. [ 2 , 3 , 4 , 5 , 6 ].

1. Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control. Mol. Cell 6, 637-48
2. DnaA, ORC, and Cdc6: similarity beyond the domains of life and diversity. Biochem. Cell Biol. 88, 49-62
3. The origin recognition complex protein family. Genome Biol. 10, 214
4. CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Carcinogenesis 29, 237-43
5. Down to the origin: Cdc6 protein and the competence to replicate. Trends Cell Biol. 13, 110-3
6. The role and regulation of the preRC component Cdc6 in the initiation of premeiotic DNA replication. Mol. Biol. Cell 15, 2230-42