Eukaryotic replisome assembly and initiation of the DNA synthesis at individual origins require actions of many proteins and critically depend on activities of S-phase cyclin-dependent kinases (S-CDKs) and Cdc7-Dbf4. Both types of heterodimeric kinases are regulated by their respective activating subunits (cyclins and Dbf4), which oscillate during the cell cycle.
The most characterised role of Cdc7-Dbf4 is phosphorylation of the MCM2-7 complex, required to trigger its DNA helicase activity. Due to its essential role in DNA replication, Cdc7-Dbf4 has been put forward as a target for the development of anti-cancer drugs.
We use x-ray crystallography and complementary approaches to gain structural insights in the initiation of DNA replication. Recently we determined the first crystal of Cdc7-Dbf4 kinase, which elucidated the basis for binding to and activation of Cdc7 by Dbf4 and provided a framework for design of more potent and specific Cdc7 inhibitors.
We are now focusing on the mechanisms of regulation of Cdc7 activity and other structural aspects of initiation of eukaryotic DNA replication.