In vivo transposition mediated by V(D)J recombinase in human T lymphocytes
In vivo transposition mediated by V(D)J recombinase in human T lymphocytes
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DOI：
10.1093/emboj/cdg137
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发表时间：
2003-03-17
期刊：
影响因子：
11.4
通讯作者：
Finette, BA
中科院分区：
文献类型：
--
作者：
Messier, TL;O'Neill, JP;Finette, BA
免疫球蛋白（IG）和T细胞受体（TCR）基因在淋巴细胞中通过V（D）J重组酶的重排是人类免疫多样性所必需的。这些DNA重排涉及RAG 1和RAG 2（RAG 1/2）重组酶在重组信号序列（RSS）处的切割。该反应产生两种产物，裂解的信号末端和编码末端。编码末端通过非同源末端连接蛋白连接以形成功能性IG或TCR基因产物，而信号末端形成信号接头。体外研究已经证明RAG 1/2能够介导切割的信号末端转座到靶DNA分子的非特异性位点。然而，迄今为止，在体内转座的信号末端尚未得到证实。我们目前的证据，在体内染色体间转座在人类介导的V（D）J重组酶。T细胞分离株显示含有插入X-连锁次黄嘌呤-鸟嘌呤磷酸核糖转移酶基因座的来自14号染色体的TCR α信号末端，导致基因失活。这些发现暗示V（D）J重组酶介导的转座作为一种诱变机制，能够在人类有害的遗传重排。
The rearrangement of immunoglobulin (Ig) and T-cell receptor (TCR) genes in lymphocytes by V(D)J recombinase is essential for immunological diversity in humans. These DNA rearrangements involve cleavage by the RAG1 and RAG2 (RAG1/2) recombinase enzymes at recombination signal sequences (RSS). This reaction generates two products, cleaved signal ends and coding ends. Coding ends are ligated by non-homologous end-joining proteins to form a functional Ig or TCR gene product, while the signal ends form a signal joint. In vitro studies have demonstrated that RAG1/2 are capable of mediating the transposition of cleaved signal ends into non-specific sites of a target DNA molecule. However, to date, in vivo transposition of signal ends has not been demonstrated. We present evidence of in vivo inter-chromosomal transposition in humans mediated by V(D)J recombinase. T-cell isolates were shown to contain TCRalpha signal ends from chromosome 14 inserted into the X-linked hypo xanthine-guanine phosphoribosyl transferase locus, resulting in gene inactivation. These findings implicate V(D)J recombinase-mediated transposition as a mutagenic mechanism capable of deleterious genetic rearrangements in humans.