The Mre11 complex: linking recombination to checkpoints

在本提案中，我们将继续利用第一个资助期建立的小鼠品系，以解决Mre 11复合物在染色体代谢中的作用机制。此外，我们将测试的假设，即蛋白质相互作用的Nbs1 N末端的DNA损伤反应的调节是至关重要的。我们希望这些方法将继续提供重要的见解Mre11复合物在维持基因组完整性和抑制恶性肿瘤的作用。该提议的主导假设是，从其与染色质的关联来看，Mre 11复合物作为DNA损伤反应的中心发挥作用。我们认为，这种关联是其影响DSB修复和DNA损伤信号传导过程中姐妹染色单体相互作用的先决条件。此外，我们提出，它的信号传导功能发生通过蛋白质相互作用，包括那些由N末端的Nbs1。我们将通过在人类细胞和小鼠中结合生物化学和遗传学方法来测试这些假设。

In this proposal, we will continue to exploit the mouse strains established in the first funding period to address the mechanisms of the Mre11 complex's actions in chromosome metabolism. In addition, we will test the hypothesis that proteins interacting with the Nbs1 N terminus are critical for regulation of DNA damage responses. We expect that these approaches will continue to provide important insights regarding the role of the Mre11 complex in the maintenance of genomic integrity and the suppression of malignancy. The governing hypothesis of this proposal is that, from its association with chromatin, the Mre11 complex functions as a hub of the DNA damage response. We propose that this association is a prerequisite for its influence on sister chromatid interaction during DSB repair and DNA damage signaling. In addition, we propose that its signaling function takes place via protein interactions that include those governed by the N terminus of Nbs1. We will test these hypotheses through a combination of biochemical and genetic approaches in human cells and mice.