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DNA replication is initiated by assembling pre-replicative complex (pre-RC), and DNA replicative protein Cdc6 plays a central role in the initiation of DNA replication. As cells enter G1 from mitosis, Cdc6, together with Cdt1 are recruited to the replicating origins bound with six components of origin recognition complex (ORC) (Dutta and Bell, 1997; Mendez and Stillman, 2000). The pre-RC is formed by loading minichromosome maintenance proteins (MCMs) along with other replicating proteins onto origins, and Cdc6 controls the loading. The stability of Cdc6 during G1 is a key step to regulate pre-RC assembly. Cdc6 is targeted to ubiquitin-mediated proteolysis by the anaphase promoting complex (APC) in G1. The cyclindependent kinase (CDK), specifically, cyclin E-Cdk2 kinase is responsible for phosphorylation of human Cdc6, and Cdc6 is stabilized with its amino-terminal end phosphorylated (Mailand and Diffley, 2005). The Cdc6 phosphorylation by CDKs ensures that origin is fired at S phase, and DNA is replicated only once per S phase. Human Cdc6 is also involved in G2/M phase checkpoint as overexpression of Cdc6 in G2 blocks HeLa cell into mitosis (Clay-Farrace et al., 2003). More recently, human Cdc6 shows to play a role in late S phase and S-G2/M transition in controlling cell cycle progression (Lau et al., 2006). These studies suggest that human Cdc6 functions beyond its essential role in the initiation of DNA replication. Senescence is an irreversible cell event with permanent G1 arrest. Senescent normal somatic cells show features such as the permanent arrest of proliferation, repression of telomerase reverse transcriptase (TERT) expression, and expression of senescence associated-βgalactosidase (SA-β-Gal). The lack of TERT activities has been observed in most human somatic cells and is linking to replicative senescence (Campisi, 2001). Replicative senescence occurs with functional p53 and p16INK4a–Rb pathway (Campisi, 2001; Beausejour et al., 2003). Accumulated evidence shows that tumor cells experience p53 mutation, p16INK4a or Rb inactivation or deletion, accompanied with the re-expression of TERT. Evidence shows that senescence normal fibroblasts undergo the formation of senescence-associated heterochromatic foci (SAHF), and trior di-methylation of lysine 9 on histone H3 (H3K9me3/me2) has been found in the SAHF (Narita et al., 2003, 2006).

Cdc6 Knockdown Renders p16INK4a Re-Activation, Leading to Senescence Human Breast Carcinoma Cells