Role of the Mre11 complex in the maintenance of genome stability

 描述(申请人提供)：mre11复合体由mre11、Rad50和Nbs1亚基(MRN)组成，对维持基因组的稳定性是必不可少的。Nbs1和Mre11分别与奈梅根破裂综合征(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复合体在DNA损伤反应和DNA双链断裂(DSB)修复中起着关键作用，但其潜在的机制尚不完全清楚。在这项研究中，我们发现了Mre11复合体在常见的脆性位点保护、复制分叉保护和DSB修复中的新功能。我们建议进一步研究Mre11复合体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复合体在保护常见脆弱部位稳定性中的作用。我们将使用新建立的检测方法来检查常见的脆弱部位保护，并探索MRN维持叉子稳定性和修复常见脆弱部位产生的DSB的机制。其次，我们将研究Mre11复合体保护停滞的复制分叉的功能 并通过与其他分叉稳定蛋白的特定相互作用，促进修复偶联复制在折叠的分叉重新开始。第三，我们将研究Mre11复合体如何调节DSB末端的末端切除，并调节修复DSB的适当途径的利用。这些研究将揭示Mre11复合体在维持基因组稳定性方面关键功能的分子机制，并将为MRN缺陷如何导致受影响个体癌症的分子基础以及维持基因组稳定性如何有助于预防人类肿瘤的发生提供见解。

 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.