Analysis of vertebrate cyclin dependent kinase function in genome maintenance by chemical genetics. (360G-Wellcome-082267_Z_07_Z)

I am planning to investigate how Cdks coordinate DNA replication and repair to ensure the maintenance of a stable genome. Cdks are known to trigger DNA replication, but little is known on Cdk function at later stages of S-phase. To address this question I have established a vertebrate cellular model system, in which S-phase is controlled by a single allel of a mutant Cdk1, that can be instantly turned off by the addition of a mutant-specific inhibitor. Using this system I would like to investiga te how Cdks contribute to replication fork progression in the absence or presence of DNA damage; I would also like to address the control of DNA double strand break repair by Cdks. Furthermore I am planning to combine this chemical genetics system with a proteomics approach to identify the relevant targets of Cdks in these pathways. If successful this study will clarify how the major pathways of genome maintenance are coordinated by Cdks to ensure a successful duplication of the genome during th e S-phase of vertebrate cells.