The Mre11 complex: linking recombination to checkpoints

在这项提案中，我们将继续利用在第一个资助期建立的小鼠品系来解决Mre11复合体在染色体新陈代谢中的作用机制。此外，我们将检验与Nbs1N末端相互作用的蛋白质对调节DNA损伤反应至关重要的假设。我们期望这些方法将继续提供关于mre11复合体在维持基因组完整性和抑制恶性肿瘤中的作用的重要见解。这一提议的主导假设是，从它与染色质的联系来看，Mre11复合体作为DNA损伤反应的中心发挥作用。我们认为，这种联系是其在DSB修复和DNA损伤信号转导过程中影响姐妹染色单体相互作用的先决条件。此外，我们认为它的信号功能是通过蛋白质相互作用实现的，其中包括由Nbs1的N末端控制的蛋白质相互作用。我们将在人类细胞和小鼠身上通过生化和遗传方法的组合来检验这些假说。

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.