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

描述(申请人提供)：mre11/Rad50/Nbs1复合体(MRN)在维持基因组稳定性中起关键作用。NBS和ATLD患者细胞都显示血细胞中染色体易位增加，但机制尚不清楚。在这一修订应用中，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的哪些功能对于防止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在复制应激下DSB修复中的作用，并将其功能与其在防止染色体易位中的作用联系起来。阐明MRN在预防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从头癌症和治疗相关癌症。 公共卫生相关性：染色体易位与癌症的发展高度相关。Nbs1(Nijmegen Break综合征)和Mre11(共济失调-毛细血管扩张样疾病)缺陷的患者都表现出更高的染色体易位水平和更高的淋巴样肿瘤发生风险。了解Mre11/Rad50/Nbs1复合体在防止染色体易位中的作用将有助于阐明维持基因组稳定的细胞机制，并最终有助于开发预防癌症的治疗干预措施。这一修订申请是对美国国立卫生研究院宣布恢复法案资金可用的回应。我们将主要使用预算来创造新的就业机会。

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.