Howard Hughes Medical Institute, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0648, USA.
Cell. 2009 Dec 11;139(6):1069-83. doi: 10.1016/j.cell.2009.11.030.
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 androgen receptor (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 activities induced by genotoxic stress and liganded AR, including activation-induced cytidine deaminase and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymes synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by nonhomologous end joining pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded nuclear receptor and genotoxic stress underlies nonrandom tumor translocations, which may function in many types of tumors and pathological processes.
染色体易位是白血病/淋巴瘤的一个标志，也出现在实体肿瘤中，但潜在的机制仍难以捉摸。通过建立一种细胞模型，该模型模拟了没有增殖选择的真实易位事件的相对频率，我们报告了核受体依赖性肿瘤易位的机制。配体结合的雄激素受体 (AR) 通过触发染色体内和染色体间相互作用，首先将易位基因座连接在一起。然后，AR 通过招募两种由遗传毒性应激和配体 AR 诱导的酶活性来促进易位基因座的特异性 DNA 双链断裂 (DSB)，包括激活诱导的胞嘧啶脱氨酶和 LINE-1 重复编码的 ORF2 内切酶。这些酶协同作用在易位基因座产生位点选择性 DSB，这些 DSB 通过非同源末端连接途径连接，用于特定的易位。我们的数据表明，配体结合的核受体和遗传毒性应激启动的两个平行途径的融合是无规则肿瘤易位的基础，这可能在许多类型的肿瘤和病理过程中发挥作用。
