A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex
A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex
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DOI：
10.1038/nature02355
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发表时间：
2004-03-04
期刊：
影响因子：
64.8
通讯作者：
Lieber, MR
中科院分区：
文献类型：
--
作者：
Raghavan, SC;Swanson, PC;Lieber, MR
生物体体细胞中自发染色体易位的原因在很大程度上是未知的，尽管在所有提出的机制中都需要双链DNA断裂（1-5）。(.)人类癌症中最常见的染色体异常是14号和18号染色体之间的相互易位（t（14;18）），其发生在滤泡性淋巴瘤中。14号染色体上免疫球蛋白重链位点的断裂是正常V（D）J重组过程的中断。但是，18号染色体上Bcl-2基因的断裂发生在一个150个碱基对的区域内（主要断裂点区域或Mbr），其原因仍然是个谜。我们已经复制了在人类细胞中繁殖的附加体上的易位过程的关键特征。RAG复合物是V、D或J片段DNA切割的正常酶，它以反映染色体易位模式的方式在体外和体内切割Bcl-2 Mbr;然而，Mbr不是V（D）J重组信号。相反，Bcl-2 Mbr在20-30%的等位基因处呈现人类细胞染色体内的非B型DNA结构。假设这种结构的纯化DNA含有单链的稳定区域，其与患者中的易位区域很好地对应。因此，人类基因组中稳定的非B-DNA结构似乎是Bcl-2 Mbr脆性的基础，而RAG复合物能够切割该结构。
The causes of spontaneous chromosomal translocations in somatic cells of biological organisms are largely unknown, although double-strand DNA breaks are required in all proposed mechanisms(1-5).(.) The most common chromosomal abnormality in human cancer is the reciprocal translocation between chromosomes 14 and 18 (t(14;18)), which occurs in follicular lymphomas. The break at the immunoglobulin heavy-chain locus on chromosome 14 is an interruption of the normal V(D)J recombination process. But the breakage on chromosome 18, at the Bcl-2 gene, occurs within a confined 150-base-pair region (the major breakpoint region or Mbr) for reasons that have remained enigmatic. We have reproduced key features of the translocation process on an episome that propagates in human cells. The RAG complex-which is the normal enzyme for DNA cleavage at V, D or J segments-nicks the Bcl-2 Mbr in vitro and in vivo in a manner that reflects the pattern of the chromosomal translocations; however, the Mbr is not a V(D)J recombination signal. Rather the Bcl-2 Mbr assumes a non-B-form DNA structure within the chromosomes of human cells at 20-30% of alleles. Purified DNA assuming this structure contains stable regions of single-strandedness, which correspond well to the translocation regions in patients. Hence, a stable non-B-DNA structure in the human genome appears to be the basis for the fragility of the Bcl-2 Mbr, and the RAG complex is able to cleave this structure.