CDC6

CDC6 (Cell Division Cycle 6) is a protein that plays a crucial role in the initiation of DNA replication in eukaryotic cells. It is a member of the pre-replicative complex (pre-RC) that assembles at replication origins during the G1 phase of the cell cycle and is necessary for the formation of the replication fork during the S phase. CDC6 works closely with other proteins such as Origin Recognition Complex (ORC), Cdt1, and MCM proteins to ensure that DNA replication is initiated accurately and only once per cell cycle.

Function

CDC6 is primarily involved in the early stages of DNA replication. It binds to the ORC complex, which has already attached to the replication origins in the chromatin. The binding of CDC6 is a critical step that facilitates the recruitment of Cdt1 and MCM proteins, forming the pre-RC. The MCM complex then serves as the helicase, unwinding the DNA helix and allowing replication forks to form and initiate DNA synthesis. The activity and stability of CDC6 are tightly regulated by phosphorylation and proteolysis, ensuring that replication occurs only once per cell cycle.

Regulation

The regulation of CDC6 is complex and involves multiple mechanisms to prevent re-replication. During the G1 phase, CDC6 is stabilized and active, allowing the assembly of pre-RCs. However, as cells progress into the S phase, CDC6 is phosphorylated by Cyclin-dependent kinases (CDKs), which leads to its export from the nucleus or targeting for degradation. This phosphorylation acts as a fail-safe mechanism to prevent the re-initiation of replication within a single cell cycle.

Clinical Significance

Alterations in the regulation of CDC6 have been implicated in the development of cancer. Overexpression of CDC6 can lead to genomic instability, a hallmark of cancer cells, by promoting re-replication and thus DNA damage. As such, CDC6 is considered a potential target for cancer therapy, with research focused on understanding its role in tumorigenesis and exploring ways to modulate its activity in cancer cells.

See Also

• Cell cycle
• DNA replication
• Oncogene