Cdc6

Cdc6 is a protein that plays a crucial role in the initiation of DNA replication in eukaryotic cells. It is an essential component 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 functions alongside other key 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's primary role is to regulate the assembly of the pre-RC at replication origins. It acts after the ORC has bound to the DNA by recruiting Cdt1 and MCM helicase complexes, thereby completing the pre-RC. The MCM complex is crucial for unwinding the DNA helix, allowing replication machinery to access the single-stranded DNA. Cdc6, therefore, is pivotal in the transition from the G1 to the S phase of the cell cycle, ensuring that each segment of the genome is replicated once and only once.

Regulation

The activity and stability of Cdc6 are tightly regulated by multiple mechanisms, including phosphorylation and proteolysis. Phosphorylation of Cdc6 by Cyclin-dependent kinases (Cdks) and Dbf4-dependent kinase (DDK) serves as a regulatory mechanism to prevent re-replication. Phosphorylated Cdc6 is either exported from the nucleus or targeted for degradation, ensuring that pre-RC assembly does not occur again within the same cell cycle.

Clinical Significance

Alterations in Cdc6 expression or function have been implicated in the pathogenesis of various cancers. Overexpression of Cdc6 can lead to uncontrolled cell proliferation due to deregulation of DNA replication, contributing to genomic instability, a hallmark of cancer cells. Therefore, Cdc6 is considered a potential target for cancer therapy, with research focused on developing inhibitors that can modulate its activity.

Evolutionary Conservation

Cdc6 is evolutionarily conserved across eukaryotes, highlighting its fundamental role in DNA replication. Studies in model organisms, such as yeast and Xenopus, have contributed significantly to understanding Cdc6's function and regulation. These studies underscore the conserved mechanism of DNA replication initiation across different species.

See Also

• Cell cycle
• DNA replication
• Origin Recognition Complex
• MCM proteins