V(D)J Recombination: Mechanism, Errors, and Fidelity.
V(D)J Recombination: Mechanism, Errors, and Fidelity.
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DOI：
10.1128/microbiolspec.mdna3-0041-2014
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发表时间：
2014-12
影响因子：
3.7
通讯作者：
Roth DB
中科院分区：
文献类型：
--
作者：
Roth DB
半个多世纪前，人们认识到 B 细胞可以产生针对多种化学结构的抗体，这引发了人们对“多样性的产生”问题的浓厚兴趣（参考文献 1 进行了综述）。这个难题的正确解决方案既令人惊讶又简单：编码受体抗原结合部分（所谓的可变区）的外显子是通过染色体断裂组装的，并在发育中的淋巴细胞中重新连接 (2)。免疫球蛋白和 T 细胞受体由两条多肽链组成，每条多肽链都构成抗原结合结构域。编码抗原结合结构域的外显子是通过“剪切和粘贴”DNA 重排从所谓的 V（可变）、D（多样性）和 J（连接）基因片段组装而成。这个过程被称为 V(D)J 重组，选择一对片段，在每个片段附近引入双链断裂，删除（或在某些情况下，反转）插入的 DNA，并将片段连接在一起（图 1）。重新排列以有序的方式发生，在 V 片段连接到重新排列的 D-J 片段之前，先进行 D-to-J 连接。这种组合组装的过程——从几种（有时是多种）可能性中选择每种类型的一个片段——是驱动哺乳动物抗原受体多样性的基本引擎。不同片段之间连接处的特征变异（少量核苷酸的丢失或增加）极大地放大了多样性。这一过程利用对种系编码能力的相对较小的投资，将其转化为几乎无限的潜在抗原结合特异性。
The realization, now more than half a century ago, that B cells can generate antibodies to an astounding variety of chemical structures sparked intense interest in the “generation of diversity” question (reviewed in reference1). The correct solution to this puzzle turned out to be both surprising and simple: the exons encoding the antigen‐binding portions of the receptor (the so‐called variable regions) are assembled by chromosomal breakage and rejoining in developing lymphocytes (2). Immunoglobulins and T‐cell receptors are composed of two polypeptide chains, each of which contributes to the antigen‐binding domain. The exons encoding the antigen‐binding domains are assembled from so‐called V (variable), D (diversity), and J (joining) gene segments by “cut and paste” DNA rearrangements. This process, termed V(D)J recombination, chooses a pair of segments, introduces double‐strand breaks adjacent to each segment, deletes (or, in selected cases, inverts) the intervening DNA, and ligates the segments together (Fig. 1). Rearrangements occur in an ordered fashion, with D‐to‐J joining proceeding before a V segment is joined to the rearranged D‐J segments. This process of combinatorial assembly—choosing one segment of each type from several (sometimes many) possibilities—is the fundamental engine driving antigen‐receptor diversity in mammals. Diversity is tremendously amplified by the characteristic variability at the junctions (loss or gain of small numbers of nucleotides) between the various segments. This process leverages a relatively small investment in germline coding capacity into an almost limitless repertoire of potential antigen‐binding specificities.