Chromothripsis and Kataegis Induced by Telomere Crisis.
Chromothripsis and Kataegis Induced by Telomere Crisis.
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DOI：
10.1016/j.cell.2015.11.054
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发表时间：
2015-12-17
期刊：
影响因子：
64.5
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Maciejowski J;Li Y;Bosco N;Campbell PJ;de Lange T
端粒危象发生在肿瘤发生过程中，当端粒储备耗尽导致频繁的端粒融合时。由此产生的双着丝粒染色体被认为是导致基因组不稳定的原因。在这里，我们研究的命运双着丝粒人类染色体端粒危机。我们观察到双着丝粒染色体在有丝分裂中始终存在，并发育成50-200 μm的染色质桥连接子细胞。在分裂后期3-20 h解体前，染色质桥在分裂间期引起核膜破裂，积累胞质3'端核酸酶TREX 1，形成RPA包被的单链DNA。CRISPR敲除表明TREX 1有助于ssDNA的产生和染色质桥的解析。危机后的克隆显示chromothripsis和kataegis，可能是由于DNA修复和APOBEC编辑片段化的染色质桥DNA。我们认为，人类癌症中的染色体断裂可能是通过TREX 1介导的端粒危象中形成的双着丝粒染色体的断裂而产生的。
Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 h after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.