Role of the Mre11 complex in the maintenance of genome stability

 描述（申请人提供）：Mre11复合物由Mre11、Rad50和Nbs1亚基（MRN）组成，对于维持基因组稳定性至关重要。 Nbs1 和 Mre11 分别与奈梅亨断裂综合征 (NBS) 和共济失调毛细血管扩张样疾病 (ATLD) 有关，受影响的患者容易患癌症。 Mre11 复合物在 DNA 损伤反应和 DNA 双链断裂 (DSB) 修复中发挥着关键作用，但其潜在机制尚不完全清楚。在这项研究中，我们发现了Mre11复合物在常见脆弱位点保护、复制叉保护和DSB修复方面的新功能。我们建议进一步研究 Mre11 复合物在维持哺乳动物细胞基因组完整性和促进 DNA DSB 修复方面的作用机制。 首先，我们将确定Mre11复合物在保护常见脆弱位点稳定性中的作用。我们将使用新建立的检测方法来检查常见脆弱位点的保护，并探索 MRN 维持叉稳定性和修复常见脆弱位点生成的 DSB 的机制。其次，我们将研究Mre11复合物保护停滞复制叉的功能 并通过与其他叉稳定蛋白的特定相互作用，促进修复耦合复制在塌陷的叉处重新启动。第三，我们将研究 Mre11 复合物如何调节 DSB 末端的末端切除并调节适当途径的利用来修复 DSB。 这些研究将揭示 Mre11 复合物在维持基因组稳定性中关键功能的分子机制，并将深入了解 MRN 缺陷如何导致受影响个体发生癌症以及维持基因组稳定性如何有助于预防人类肿瘤发生的分子基础。

 DESCRIPTION (provided by applicant): The Mre11 complex, composed of Mre11, Rad50 and Nbs1 subunits (MRN), is essential for the maintenance of genome stability. Nbs1 and Mre11 are linked to the Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively, and the affected patients are predisposed to cancer. The Mre11 complex plays a critical role in DNA damage response and DNA double-strand break (DSB) repair, but the underlying mechanisms are not fully understood. In this study, we identified new functions of the Mre11 complex in common fragile site protection, replication fork protection and DSB repair. We propose to further investigate the mechanisms underlying the role of the Mre11 complex in preserving genome integrity and promoting DNA DSB repair in mammalian cells. First, we will determine the role of the Mre11 complex in the protection of common fragile site stability. We will use newly established assays to examine common fragile site protection and explore the mechanisms of MRN to maintain fork stability and repair DSBs generated at common fragile sites. Second, we will study the function of the Mre11 complex to protect stalled replication forks and to promote repair-coupled replication restart at collapsed forks through specific interactions with other fork stabilizing proteins. Third, we will investigate how the Mre11 complex modulates end resection at DSB ends and regulates the utilization of appropriate pathways to repair DSBs. These studies will reveal the molecular mechanisms underlying the critical functions of the Mre11 complex in the maintenance of genome stability and will provide insights into the molecular basis of how MRN deficiency leads to cancer in affected individuals and how maintenance of genome stability contributes to the prevention of tumorigenesis in humans.