Role of the Mre11 complex in the maintenance of genome stability

 描述（由申请人提供）：Mre 11复合物由Mre 11、Rad 50和Nbs 1亚基（MRN）组成，对于维持基因组稳定性至关重要。Nbs 1和Mre 11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）相关，受影响的患者易患癌症。Mre 11复合物在DNA损伤反应和DNA双链断裂（DSB）修复中起着关键作用，但其潜在机制尚未完全了解。在这项研究中，我们确定了Mre 11复合物在常见的脆性位点保护，复制叉保护和DSB修复中的新功能。我们建议进一步研究Mre 11复合物在哺乳动物细胞中保护基因组完整性和促进DNA DSB修复的作用机制。 首先，我们将确定Mre 11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的脆性位点保护，并探索MRN维持分叉稳定性和修复常见脆性位点产生的DSB的机制。其次，我们将研究Mre 11复合体保护停滞复制叉的功能 并通过与其他叉稳定蛋白的特异性相互作用促进修复偶联复制在折叠叉处重新启动。第三，我们将研究Mre 11复合体如何调节DSB末端的末端切除，并调节适当途径的利用以修复DSB。 这些研究将揭示Mre 11复合物在维持基因组稳定性方面的关键功能的分子机制，并将深入了解MRN缺乏如何导致受影响个体的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.