Cell cycle regulation of DNA replication initiator factor Dbf4p

The precise duplication of eukaryotic genetic material takes place once and only once per cell cycle and is dependent on the completion of the previou s mitosis, Two evolutionarily conserved kinases, the cyclin B (Clb)/cyclin- dependent kinase (Cdk/Cdc28p) and Cdc7p along with its interacting factor D bf4p, are required late in G(1) to initiate DNA replication. We have determ ined that the levels of Dbf4p are cell cycle regulated. Dbf4p levels increa se as cells begin S phase and remain high through late mitosis, after which they decline dramatically as cells begin the next cell cycle. We report th at Dbf4p levels are sensitive to mutations in key components of the anaphas e-promoting complex (APC), In addition, Dbf4p is modified in response to DN A damage, and this modification is dependent upon the DNA damage response p athway. We had previously shown that Dbf4p interacts with the M phase polo- like kinase Cdc5p, a key regulator of the APC late in mitosis, These result s further link the actions of the initiator protein, Dbf4p, to the completi on of mitosis and suggest possible roles for Dbf4p during progression throu gh mitosis.