Dbf4

Dbf4 is the regulatory subunit of the Cdc7 kinase, forming the Dbf4-dependent kinase (DDK). In budding yeast, Dbf4 binds the catalytic subunit Cdc7 to create an active kinase essential for initiation of DNA replication. DDK phosphorylates components of the MCM2-7 helicase complex and other initiation factors, promoting replication origin firing in S phase. The Dbf4 subunit determines substrate specificity and regulates kinase activity, linking CDC7 function to cell cycle progression.

In metazoans, including humans, the DBF4 gene encodes a Dbf4-like regulatory protein that binds CDC7 to form human DDK. A related regulator, encoded by DBF4B (also called Drf1), can also pair with CDC7 to generate a second DDK complex with overlapping functions. The DDK complexes participate in origin licensing and activation, and contribute to replication stress responses and S-phase progression.

Dbf4 and its partners are typically expressed in S phase, and their activity is coordinated with other cell cycle regulators to ensure timely replication initiation. Deregulation or overexpression of CDC7 and/or its regulatory subunits has been observed in various cancers. DDK inhibitors are being explored as anti-cancer agents, with several compounds in preclinical or clinical development.