STUDIES OF IMMUNOGLOBULIN GENE REARRANGEMENT

V（D）J重组是一种DNA重排， 组装功能性免疫球蛋白和T细胞受体基因， 淋巴样细胞，并为产生的多样性， 免疫反应已知该反应分两个阶段进行。在 第一阶段，RAG1和RAG2蛋白协同作用， 在靶位点的特异性双链断裂。后面的步骤， 以新的组合连接断裂的末端，已知是 相对非特异性，并与DNA共享许多蛋白质因子 双链断裂修复 我们最近发现了一个完全 由纯化的RAG蛋白催化的不同过程，其中 DNA识别序列的断裂末端共价连接， 插入到不相关的DNA中这是一个换位 重组在所有方面都相当于经典的跳跃 转座子进入新的DNA位点，或染色体整合 逆转录病毒DNA 这种新的反应对以下方面具有广泛的影响： 免疫系统.首先，这可能有助于解释进化论中的 可变免疫反应的起源。早些时候已经注意到， 免疫多样性，DNA识别序列， RAG基因在有颌脊椎动物的水平上一起出现 (e.g.鲨鱼），没有任何低等生物的成分。 这导致了一个换位跳跃的建议， 引入了RAG基因及其识别序列， 同一时间（从一个未知的生物体），但直到现在， 这些建议纯属推测。现在这是一个似是而非的 机制 第二，淋巴细胞中正在发生的易位事件 细胞可以解释一些染色体易位， 淋巴瘤已知这些易位中有许多是 与RAG基因表达相关，但与V（D）J不同 在一个DNA位点的重组没有相似性， 识别序列。一个被折断的末端的换位攻击 从免疫球蛋白或T细胞受体基因座将有 更正属性以说明这些事件。

V(D)J recombination is a DNA rearrangement that assembles functional immunoglobulin and T cell receptor genes in lymphoid cells, and is essential for generating the diversity of the immune response. The reaction is known to occur in two stages. In the first stage, the RAG1 and RAG2 proteins cooperate to make specific double-strand breaks at the target sites. The later steps, which join the broken ends in new combinations, are known to be relatively non-specific and to share many protein factors with DNA double-strand break repair. We have recently found an entirely different process catalyzed by the purified RAG proteins, in which the broken ends of the DNA recognition sequences are covalently inserted into unrelated DNA. This is a transpositional recombination in all ways equivalent to the jumping of classical transposons into new DNA sites, or to the chromosomal integration of retroviral DNA. This novel reaction has broad implications for the immune system. First, it may help to explain the evolutionary origin of the variable immune response. It has been noted earlier that immune diversity, the DNA recognition sequences, and the RAG genes appear together at the level of the jawed vertebrates (e.g. sharks), without a trace of any component in lower organisms. This had led to the suggestion of a transpositional jump that brought in both the RAG genes and their recognition sequences at the same time (from an unknown organism), but until now the suggestion had been purely speculative. Now it is a plausible mechanism. Second, ongoing transpositional events in lymphoid cells may explain some of the chromosomal translocations that lead to lymphoid tumors. Many of these translocations are known to be linked with RAG gene expression, but to differ from V(D)J recombination in that one DNA site has no similarity to the recognition sequence. A transpositional attack by a broken end from an immunoglobulin or T cell receptor locus would have the correct properties to account for these events.