Role of Telomeric Proteins in Antibody Class Switch Recombination

描述(由申请人提供)：抗体(免疫球蛋白，Ig)类开关重组(CSR)是通过有效地产生介导病原体消除的抗体亚型而使体液免疫反应多样化的基本机制。CSR是免疫球蛋白重链基因座(IGH)开关(S)区DNA双链断裂之间的程序性缺失重组事件。这些dsb是由突变酶激活诱导型胞苷脱氨酶(Aid)启动的，该酶优先定位于免疫球蛋白基因座，但也在其他基因组区域表现出非靶标活性。 包括原癌基因。因此，如果不正确修复，AID在基因组非靶区启动的双链断裂很容易导致异常重组事件和IgH基因与癌基因之间的染色体易位。事实上，这种基因组异常是B细胞恶性肿瘤的一个标志。然而，定义B细胞如何控制由AID引发的DNA损伤修复的分子机制还知之甚少。因此，我们的研究计划的目标是表征我们已经确定的调控AID在CSR期间启动的DNA损伤修复的新的分子机制。我们最近发现，端粒蛋白TRF2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，它也是CSR所必需的。在此，我们建议进一步研究TRF2调控CSR的分子机制，其具体目的如下：1.鉴定和鉴定在CSR过程中受TRF2调控的特定DDR蛋白。2.剖析了TRF2在CSR过程中控制DNA修复的分子机制。3.阐明在CSR过程中TRF2与IgH基因的相互作用。综上所述，这些研究将提供一种新的机制的具体细节，该机制调节B细胞的免疫多样化和在AID激活期间维持基因组的稳定性。

DESCRIPTION (provided by applicant): 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 (DSBs) at switch (S) regions in the Ig heavy chain gene locus (Igh). These DSBs are initiated by the mutagenic enzyme, activation-induced cytidine deaminase (AID), which preferentially localizes at Igh loci but also exhibits off-target activity in other genomic regions including proto-oncogenes. Hence, DSBs initiated by AID in off-target regions of the genome can readily lead to aberrant recombination events and chromosome translocations between the Igh locus and oncogenes if not correctly repaired. Indeed, such genomic aberrations are a hallmark of B-cell malignancies. However the molecular mechanisms that define how B-cells control the repair of DNA lesions initiated by AID are poorly understood. 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. 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. Identify and characterize the specific DDR proteins regulated by TRF2 during CSR. 2. Dissect the molecular mechanisms used by TRF2 to control DNA repair during CSR. 3. Elucidate how TRF2 interacts with the Igh locus during CSR. 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.