Jones Jessica M, Simkus Carrie
Department of Biochemistry and Molecular and Cellular Sciences, Georgetown University Medical Center, Washington, DC 20007, USA.
Arch Immunol Ther Exp (Warsz). 2009 Mar-Apr;57(2):105-16. doi: 10.1007/s00005-009-0011-3. Epub 2009 Mar 31.
The enormous repertoire of the vertebrate specific immune system relies on the rearrangement of discrete gene segments into intact antigen receptor genes during the early stages of B-and T-cell development. This V(D)J recombination is initiated by a lymphoid-specific recombinase comprising the RAG1 and RAG2 proteins, which introduces double-strand breaks in the DNA adjacent to the coding segments. Much of the biochemical research into V(D)J recombination has focused on truncated or "core" fragments of RAG1 and RAG2, which lack approximately one third of the amino acids from each. However, genetic analyses of SCID and Omenn syndrome patients indicate that residues outside the cores are essential to normal immune development. This is in agreement with the striking degree of conservation across all vertebrate classes in certain non-core domains. Work from multiple laboratories has shed light on activities resident within these domains, including ubiquitin ligase activity and KPNA1 binding by the RING finger domain of RAG1 and the recognition of specific chromatin modifications as well as phosphoinositide binding by the PHD module of RAG2. In addition, elements outside of the cores are necessary for regulated protein expression and turnover. Here the current state of knowledge is reviewed regarding the non-core regions of RAG1 and RAG2 and how these findings contribute to our broader understanding of recombination.
脊椎动物特异性免疫系统的庞大基因库依赖于在B细胞和T细胞发育早期将离散的基因片段重排为完整的抗原受体基因。这种V(D)J重组由一种淋巴样特异性重组酶启动，该重组酶由RAG1和RAG2蛋白组成，它在与编码片段相邻的DNA中引入双链断裂。许多关于V(D)J重组的生化研究都集中在RAG1和RAG2的截短或“核心”片段上，每个片段都缺少大约三分之一的氨基酸。然而，对重症联合免疫缺陷（SCID）和奥门综合征患者的基因分析表明，核心区域之外的残基对正常免疫发育至关重要。这与所有脊椎动物类群中某些非核心结构域的高度保守程度一致。多个实验室的研究揭示了这些结构域中的活性，包括RAG1的环指结构域的泛素连接酶活性和与KPNA1的结合，以及RAG2的PHD模块对特定染色质修饰的识别以及磷酸肌醇结合。此外，核心区域之外的元件对于调节蛋白质表达和周转是必要的。本文综述了关于RAG1和RAG2非核心区域的当前知识状态，以及这些发现如何有助于我们更广泛地理解重组。
