Role of TRF2 in DNA recombination

抗体(免疫球蛋白，Ig)类开关重组(CSR)是一种重要的免疫调节机制。 通过高效产生抗体亚型来实现体液免疫应答的多样化 消除病原体。CSR是DNA双链之间的程序性缺失重组事件 免疫球蛋白重链基因座(IgH)的断裂。这些DNA断裂是由诱变酶启动的， 激活诱导胞苷脱氨酶(AID)，它优先脱氨基免疫球蛋白基因，但也表现出 包括原癌基因在内的非免疫球蛋白基因的“脱靶”活性。因此，AID在非靶点启动的DNA断裂 基因组的某些区域会导致IgH基因座和癌基因之间的异常染色体易位，如果 没有正确修复。事实上，这种基因组异常是B细胞恶性肿瘤的一个标志。相应地， 我们的研究计划的目标是表征我们已经确定的调节 CSR期间由AID引发的DNA损伤修复。我们最近发现端粒蛋白TRF2， 这对于保护染色体末端免受DNA修复活动的影响是必不可少的，对于CSR也是必要的。我们 假设TRF2对参与DNA加工的DNA修复蛋白的活性是必需的 在类切换重组过程中由AID发起的中断。在这里，我们建议扩大我们的研究范围，以确定 并描述了TRF2通过以下特定的途径控制CSR的分子机制 目标： 1.确定类转换过程中受TRF2调控的DNA修复蛋白。 2.确定TRF2在类转换过程中控制DNA修复的分子机制。 3.阐明TRF2抑制IgH-cMYC易位形成的机制。 综上所述，这些研究将为调节免疫的新机制提供具体细节 在AID激活过程中B细胞的多样化和基因组稳定性的维持。

Antibody (immunoglobulin, Ig) class switch recombination (CSR) is an essential mechanism for the diversification of humoral immune response through efficient generation of antibody isotypes that mediate elimination of pathogens. CSR is a programmed deletional recombination event between DNA double strand breaks in the Ig heavy chain gene locus (Igh). These DNA breaks are initiated by the mutagenic enzyme, activation-induced cytidine deaminase (AID), which preferentially deaminates the Igh genes but also exhibits ‘off-target’ activity in non-Ig genes including proto-oncogenes. Hence, DNA breaks initiated by AID in off-target regions of the genome lead to aberrant chromosome translocations between the Igh locus and oncogenes if not correctly repaired. Indeed, such genomic aberrations are a hallmark of B cell malignancies. Accordingly the goal of our research proposal is to characterize novel molecular mechanisms we have identified that regulate the repair of DNA lesions initiated by AID during CSR. We recently discovered that the telomeric protein TRF2, which is essential for protecting chromosome ends from DNA repair activity, is also needed for CSR. We hypothesize that TRF2 is essential for the activity of DNA repair proteins involved in the processing of DNA breaks initiated by AID during class switch recombination. Here we propose to extend our studies to identify and characterize the molecular mechanisms utilized by TRF2 to control the CSR via the following specific aims: 1. Determine the DNA repair proteins regulated by TRF2 during class switching. 2. Determine the molecular mechanisms used by TRF2 to control DNA repair during class switching. 3. Elucidate the mechanism by which TRF2 inhibits the formation of Igh-cmyc translocations. Taken together, these studies will provide specific details into a novel mechanism that regulates immune diversification in B cells and the maintenance of the genome stability during AID activation.