Cell cycle control of DNA double strand break repair and the role of Cdk

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Our genetic material is subject to damage: double-stranded DNA can become broken in both strands, fracturing chromosomes. Such double-stand breaks (DSBs) must be repaired as accurately as possible; failed or incorrectly controlled repair will lead to scrambling of the genetic material and contribute to the development of genetic disease, including cancer, and to the ageing process. Understanding the repair processes is also important because many biotechnological and therapeutic techniques involve delivering DNA to cells, and the fate of this DNA is determined by the cells' DSB repair machinery. It is proposed here to investigate how the two main cellular mechanisms for repairing DSBs are controlled as cells grow, duplicate and divide. The choice between the two main repair mechanisms (called NHEJ and HRR) is determined by the position of the 'cell cycle': before cells have replicated their genetic material NHEJ predominates, but during and after replication the two pathways coexists, although there is debate over the relative amounts. Regulator proteins that control the timing of DNA replication and division (called cyclin dependent kinases; Cdks) also regulate the choice between HRR and NHEJ. Cdk activity can promote or inhibit HRR at the expense of NHEJ, but is not clear exactly how, when in the cell cycle or which particular type of Cdk does what. We will develop new and improved methods to measure HRR and NHEJ at different stages of the cell cycle, and determine how two particular Cdks, Cdk1 and Cdk2 are involved.