Role of the Mre11/Rad50/Nbs1 complex in DNA damage response pathways

描述（由申请方提供）：Mre 11/Rad 50/Nbs 1复合物（MRN）在维持基因组稳定性方面发挥关键作用。NBS和ATLD患者细胞均显示血细胞中染色体易位增加，但机制尚不清楚。在本修订申请中，我们将使用新建立的易位检测系统来研究MRN在预防染色体易位中的作用。我们将研究MRN的哪些功能对于预防染色体易位是重要的。我们将分析不同机制诱导易位时的易位连接。我们将研究MRN在复制应激后DSB修复中的作用，并将MRN的这一功能与其在预防染色体易位中的作用联系起来。阐明MRN在防止染色体易位中的作用将有助于阐明易位机制，这对于理解癌症的病因学具有重要意义。这些研究还将有助于开发治疗干预措施，以预防与染色体易位相关的新发和治疗相关癌症。 公共卫生相关性：染色体易位与癌症发展高度相关。Nbs 1（奈梅亨断裂综合征）和Mre 11（共济失调-毛细血管扩张样疾病）缺陷患者均表现出染色体易位水平升高和发生淋巴肿瘤的风险升高。了解Mre 11/Rad 50/Nbs 1复合物在预防染色体易位中的作用将揭示维持基因组稳定性的细胞机制，并最终有助于开发预防癌症的治疗干预措施。此修订申请是为了响应NIH宣布的恢复法资金的可用性。我们将主要利用预算创造新的就业机会。

DESCRIPTION (provided by applicant): The Mre11/Rad50/Nbs1 complex (MRN) plays critical roles in the maintenance of genome stability. Both NBS and ATLD patient cells show increased chromosomal translocation in blood cells, but the mechanisms are not clear. In this revision application, we will use newly established translocation assay systems to study the role of MRN in the prevention of chromosomal translocation. We will investigate what functions of MRN are important for the prevention of chromosomal translocation. We will analyze translocation junctions when translocations are induced by different mechanisms. We will study the role of MRN in the repair of DSBs upon replication stress and link this function of MRN with its role in the prevention of chromosome translocation. Clarifying the role of MRN in the prevention of chromosomal translocation will significantly help elucidate the translocation mechanisms, which is of great importance to the understanding of cancer etiology. These studies will also help develop therapeutic interventions to prevent de novo and therapy-related cancers that are associated with chromosomal translocations. PUBLIC HEALTH RELEVANCE: Chromosomal translocations are highly associated with cancer development. Both Nbs1 (Nijmegen breakage syndrome) and Mre11 (ataxia-telangiectasia-like disorder) deficient patients exhibit increased level of chromosomal translocations and higher risk of developing lymphoid tumors. Understanding the role of the Mre11/Rad50/Nbs1 complex in the prevention of chromosomal translocation will shed light on the cellular mechanisms to maintain genome stability and will ultimately help develop therapeutic interventions for preventing cancers. This revision application is in response to the NIH announcement of the Availability of Recovery Act Funds. We will mainly use the budget to create new jobs.