MECHANISM OF CODING JOINT FORMATION

描述(改编自《调查者摘要》)：VDJ重组镜头 在淋巴细胞发育过程中的位置，是唯一的位点特异性重组 到目前为止在脊椎动物中发现的过程。异常的VDJ重组事件 在体内有深远的影响，并被认为是许多 淋巴瘤和白血病。抗原受体基因组装是由 共识重组信号序列(RSS)和反应可以 分为四个步骤：识别和切割DNA，然后 裂解的DNA末端的加工和连接。加入的反应是 对抗原受体基因组装以及维持染色体是必不可少的 正直。重组识别和切割的早期步骤 信号序列是由重组激活产物介导的 基因1和2(RAG1和RAG2)。RAG1或RAG2基因失活 人类或小鼠会导致严重的联合免疫缺陷。尽管速度很快 了解VDJ的识别和切割步骤的进展 重组，控制加工和连接的分子机制 这些目标在很大程度上仍然令人费解。尽管表面上很复杂， 反应中，只有四种蛋白质参与了连接过程 DNA-PKCs、Ku、XRCC4和连接酶IV。这些因素被认为是 理解调节细胞加工和连接的分子机制 DNA结束，VDJ加入。理解这一问题的主要障碍 调节DNA末端加工和连接的分子机制 V(D)J重组缺乏体外系统来研究这些反应。 我们现在已经开发出不同的无细胞系统，能够催化 发夹末端中间体的加工以及发夹的形成和连接 编码结束。我们计划使用这些新开发的体外系统来详细说明 V(D)J复合过程中发生的分子事件 反应的中间产物和产物以及涉及的蛋白质 在每一步。随着VDJ重组和DNA双链断裂修复 快速融合，显然它们有许多共同的因素，我们的 研究将有助于理解这两个重要的 进程。

DESCRIPTION (Adapted from Investigator's Abstract): VDJ recombination takes place during lymphocyte development and is the only site specific recombination process thus far identified in vertebrates. Aberrant VDJ recombination events have profound effects in vivo, and have been suggested as the cause of numerous lymphomas and leukemias. Antigen receptor gene assembly is directed by consensus recombination signal sequences (RSS) and the reaction can be separated into four steps: recognition and cleavage of the DNA followed by processing and joining of the cleaved DNA ends. The joining reaction is essential for antigen receptor gene assembly as well as to maintain chromosomal integrity. The early steps of the recognition and cleavage of the recombination signal sequences are mediated by the products of the recombination activating genes 1 and 2 (RAG1 and RAG2). Inactivation of the RAG1 or RAG2 gene in either human or mouse results in severe combined immune deficiency. Despite rapid progress in understanding the recognition and cleavage steps of the VDJ recombination, the molecular mechanisms that govern processing and joining of the ends remain largely obscure. Despite the apparent complexity of the reaction, only four proteins have been implicated in the joining process DNA-PKCs, Ku, XRCC4, and ligase IV. These factors are known to be essential for understanding the molecular mechanism that mediates processing and joining of the DNA ends and VDJ joining. The major stumbling block in understanding the molecular mechanism that mediates processing and joining of the DNA ends during V(D)J recombination was the lack of in vitro systems to study these reactions. We have now developed different cell free systems capable of catalyzing processing of hairpin end intermediates as well as formation and joining of coding ends. We plan to use these newly developed in vitro systems to detail the molecular events that occur during V(D)J recombination by characterizing the intermediates and products of the reaction as well as the proteins involved in each step. As VDJ recombination and DNA double strand break repair are rapidly converging and it is clear that they share a number of factors, our studies will contribute to the understanding of both of these important process.