DBF4dependent

Dbf4dependent, commonly referred to as DDK, is a conserved eukaryotic protein kinase complex essential for the initiation of DNA replication. It derives its name from the regulatory subunit Dbf4 (or a Dbf4-like protein); the catalytic subunit is Cdc7. In many organisms, the regulatory partner can also be Drf1, forming CDC7-DRF1 complexes in addition to CDC7-DBF4.

DDK activity rises at the G1/S transition and is required to activate replication origins. The active complex phosphorylates substrates involved in helicase activation, most notably components of the MCM2-7 helicase complex, promoting origin firing. In budding yeast, additional initiation factors such as Sld2 and Sld3 are also phosphorylated to facilitate replication initiation; in vertebrates, substrate specificity is less fully mapped but the MCM2-7 complex remains central.

Regulation occurs at multiple levels, including transcriptional control and the stability of Dbf4/Drf1, with activity coordinated to the cell cycle. Checkpoint pathways can modulate DDK to coordinate DNA replication with DNA repair processes, helping to preserve genome stability.

DDK is essential for cell proliferation, and dysregulation is linked to genomic instability and cancer. Pharmacological inhibitors of DDK, including XL413 and PHA-767491, are studied as potential anti-cancer agents; inhibition causes replication stress and S-phase arrest, with potential synergy when combined with DNA damage response inhibitors.

See also CDC7, DBF4, MCM2-7, Sld2, Sld3.