文章：

人淋巴样染色体易位的机制

Mechanisms of human lymphoid chromosomal translocations

原文发布日期：2016-05-25

DOI: 10.1038/nrc.2016.40

类型: Review Article

开放获取: 否

要点：

1. Neoplastic chromosomal translocations (and other pathological chromosomal rearrangements) can be considered in terms of a breakage phase, in which broken duplex DNA ends are generated, and then a rejoining phase. The rejoining phase is carried out by the non-homologous DNA end-joining (NHEJ) pathway.
2. In B lymphoid neoplasms, the breakage phase is often initiated by the activation-induced deaminase (AID) on the chromosome bearing the oncogene and the recombination activating gene (RAG) complex, comprised of RAG1 and RAG2, on the IgH chromosome. In T lymphoid neoplasms, the RAG complex is often responsible for the DNA breakage phase on both chromosomes.
3. For B lymphoid neoplasms, the chromosome break sites are often in hot spots, and the breaks are often near CG (that is, CpG sites) or WGCW (where W = A or T) motifs, which are sites at which AID can initiate lesions that lead to double-strand DNA breaks. AID is known to deaminate only cytosines that are within single-stranded DNA (ssDNA) regions.
4. The ssDNA in the hot spots may have various causes, which are still under investigation, such as transcriptionally induced topological tension, R-loop formation or some type of strand slippage at short repeat sequences. Concurrent expression of a low level of AID in pre-B cells, along with the usual high expression level of the RAG complex, permits translocation events in human cells in which a RAG-generated break is joined to an AID-initiated break.
5. Examples of RAG–AID-induced translocations in humans include t(14;18) translocation involving the immunoglobulin heavy (IGH) locus and the BCL2 gene. The t(11;14) translocation involving the IGH locus and the BCL1 locus (which is close to the cyclin D1 (CCND1) gene) is another example of a translocation that occurs in human lymphomas.
6. The principles discerned from lymphoid translocations are useful for considering the mechanism of chromosomal rearrangements and translocations generally. In particular, sequence motif analysis may be generally useful for assessing translocations in non-lymphoid cancer cells.

要点翻译：

1. 肿瘤染色体易位（及其他病理性染色体重排）可被理解为包含两个阶段：断裂期（产生断裂的DNA双链末端）和再接合期。再接合期由非同源DNA末端连接通路完成。
2. 在B淋巴细胞肿瘤中，断裂期通常由以下因素启动：携带癌基因的染色体上的活化诱导胞苷脱氨酶，以及IgH染色体上由RAG1和RAG2组成的重组激活基因复合体。在T淋巴细胞肿瘤中，RAG复合体通常负责两条染色体上的DNA断裂阶段。
3. 对于B淋巴细胞肿瘤，染色体断裂位点常位于热点区域，且断裂多发生在CG（即CpG位点）或WGCW基序（W代表A或T）附近，这些位点是AID可引发损伤进而导致DNA双链断裂的区域。已知AID仅对单链DNA区域内的胞嘧啶进行脱氨基作用。
4. 热点区域中单链DNA的形成可能有多种原因，目前仍在研究中，例如转录诱导的拓扑张力、R环形成或短重复序列处的某种链滑移。前B细胞中低水平AID的共表达，以及通常高表达的RAG复合体，使得人类细胞中可能发生RAG生成的断裂与AID引发的断裂相连接的重组事件。
5. 人类RAG-AID诱导易位的实例包括：涉及免疫球蛋白重链基因座与BCL2基因的t(14;18)易位。涉及IGH基因座与BCL1基因座（靠近细胞周期蛋白D1基因）的t(11;14)易位是淋巴瘤中发生的另一个易位范例。
6. 从淋巴细胞易位中总结的规律有助于普遍理解染色体重排和易位的机制。特别是序列基序分析可能对评估非淋巴细胞癌中的易位具有广泛适用性。

英文摘要：

Analysis of chromosomal translocation sequence locations in human lymphomas has provided valuable clues about the mechanism of the translocations and when they occur. Biochemical analyses on the mechanisms of DNA breakage and rejoining permit formulation of detailed models of the human chromosomal translocation process in lymphoid neoplasms. Most human lymphomas are derived from B cells in which a DNA break at an oncogene is initiated by activation-induced deaminase (AID). The partner locus in many cases is located at one of the antigen receptor loci, and this break is generated by the recombination activating gene (RAG) complex or by AID. After breakage, the joining process typically occurs by non-homologous DNA end-joining (NHEJ). Some of the insights into this mechanism also apply to translocations that occur in non-lymphoid neoplasms.

摘要翻译： 

对人类淋巴瘤中染色体易位序列位置的分析，为揭示易位机制及其发生时机提供了宝贵线索。对DNA断裂与重接机制的生化研究，使得我们能够构建淋巴样肿瘤中人类染色体易位过程的详细模型。大多数人类淋巴瘤源自B细胞，其中癌基因处的DNA断裂由活化诱导的脱氨酶（AID）启动。在许多情况下，易位的伙伴位点位于某一抗原受体基因座，该断裂由重组激活基因（RAG）复合体或AID产生。断裂后，连接过程通常通过非同源DNA末端连接（NHEJ）完成。对该机制的一些认识也适用于非淋巴样肿瘤中发生的易位。

原文链接：

Mechanisms of human lymphoid chromosomal translocations