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

我们的遗传物质会受到损害：双链DNA的两条链都会断裂，染色体也会断裂。必须尽可能准确地修复这种双位点断裂（DSB）;修复失败或控制不当将导致遗传物质混乱，并有助于遗传疾病（包括癌症）的发展和衰老过程。理解修复过程也很重要，因为许多生物技术和治疗技术涉及将DNA递送到细胞，并且这种DNA的命运由细胞的DSB修复机制决定。在这里，建议调查如何修复DSB的两个主要的细胞机制是控制细胞生长，复制和分裂。两种主要修复机制（称为NHEJ和HRR）之间的选择是由“细胞周期”的位置决定的：在细胞复制其遗传物质之前，NHEJ占主导地位，但在复制期间和之后，两种途径共存，尽管对相对量存在争议。控制DNA复制和分裂时间的调节蛋白（称为细胞周期蛋白依赖性激酶; Cdks）也调节HRR和NHEJ之间的选择。Cdk活性可以促进或抑制HRR，但以NHEJ为代价，但尚不清楚具体如何，何时在细胞周期中或哪种特定类型的Cdk做什么。我们将开发新的和改进的方法来测量HRR和NHEJ在细胞周期的不同阶段，并确定如何两个特定的Cdks，Cdk 1和Cdk 2参与。

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.