Dbf4: the whole is greater than the sum of its parts.

Together with cyclin-dependent kinases, the Dbf4-dependent kinase (DDK) is essential to activate the Mcm2-7 helicase and, hence, initiate DNA replication in eukaryotes. Beyond its role as the regulatory subunit of the DDK complex, the Dbf4 protein also regulates the activity of other cell cycle kinases to mediate the checkpoint response and prevent premature mitotic exit under stress. Two features that are unusual in DNA replication proteins characterize Dbf4. The first is its evolutionary divergence; the second is how its conserved motifs are combined to form distinct functional units. This structural plasticity appears to be at odds with the conserved functions of Dbf4. In this review, we summarize recent genetic, biochemical and structural work delineating the multiple interactions mediated by Dbf4 and its various functions during the cell cycle. We also discuss how the limited sequence conservation of Dbf4 may be an advantage to regulate the activities of multiple cell cycle kinases.