The control of the initiation step of DNA replication by proteinkinase Dbf4/Cdc7 Regulation des murinen "origin recognition complex (ORC)" durch Cyclin-Cdk-Komplexe

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Our particular long-term aim is the elucidation of the molecular mechanisms governing the onset of DNA replication at the G1/S phase transition. The project we are seeking support for will be focussed on the particular role played by the protein kinase complex Dbf4/Cdc7 during the transition from the G1 to the S phase of the cell cycle and its dependence on the mitogenic signal transduction cascade. Specifically, we will investigate the following aspects: (i) effects of interactions between Dbf4p and Cdc7p on kinase activity and structural analysis of interacting domains, (ii) analysis of phosphorylation sites in Dbf4/Cdc7p and their point mutation (iii) functional effects of phosphorylation of Dbf4/cdc7p by cyclin/Cdks and by autophosphorylation, (iv) characterization of targets of Dbf4/Cdc7p kinase activity, (v) generation of conditional knock-out mice for the analysis of functions of Dbf4/Cdc7 in cell proliferation and differentiation. We expect that these studies will lead to a general understanding of the mechanism by which Dbf4/Cdc7 contributes to initiation of DNA replication and cell cycle control.