Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.
Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.
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DOI：
10.1016/j.cell.2009.11.030
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发表时间：
2009-12-11
期刊：
影响因子：
64.5
通讯作者：
Rosenfeld MG
中科院分区：
文献类型：
--
作者：
Lin C;Yang L;Tanasa B;Hutt K;Ju BG;Ohgi K;Zhang J;Rose DW;Fu XD;Glass CK;Rosenfeld MG
染色体易位是白血病/淋巴瘤的标志，也出现在实体瘤中，但潜在的机制仍然难以捉摸。通过建立一个细胞模型，模拟真实的易位事件的相对频率没有增殖选择，我们报告的核受体依赖性肿瘤易位的机制。配体-AR的内含子结合首先通过触发染色体内和染色体间的相互作用使易位位点并置。然后，AR通过招募由遗传毒性应激和配体AR诱导的两种类型的酶机制，包括激活诱导的胞苷脱氨酶（AID）和LINE-1重复编码的ORF 2核酸内切酶，促进易位位点处的位点特异性DNA双链断裂（DSB）。这些酶机制协同地在并置的易位基因座处产生位点选择性DSB，所述易位基因座通过非同源末端连接（NHEJ）途径连接以用于特异性易位。我们的数据表明，由配体核受体和遗传毒性应激启动的两个平行途径的汇合是非随机肿瘤易位的基础，这可能在许多类型的肿瘤和病理过程中起作用。
Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear in solid tumors, but the underlying mechanism remains elusive. By establishing a cellular model that mimics the relative frequency of authentic translocation events without proliferation selection, we report mechanisms of nuclear receptor-dependent tumor translocations. Intronic binding of liganded-AR first juxtaposes translocation loci by triggering intra- and interchromosomal interactions. AR then promotes site-specific DNA double-stranded breaks (DSBs) at translocation loci by recruiting two types of enzymatic machinery induced by genotoxic stress and liganded-AR, including Activation-Induced Cytidine Deaminase (AID) and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymatic machineries synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by Non-Homologous Ending Joining (NHEJ) pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded-nuclear receptor and genotoxic stress underlie non-random tumor translocations, which may function in many types of tumors and pathological processes.
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