Telomere erosion, dysfunction, and fusion can lead to a state of cellular crisis characterized by large-scale genome instability. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole-genome sequence analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis but formed in the absence of functional nonhomologous end-joining pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness showing preferential repair to local regions or exchange between specific loci. We find evidence of telomere involvement with an enrichment of fold-back inversions demarcating clusters of rearrangements. Our data suggest that chromothriptic rearrangements caused by a telomere crisis arise via a replicative repair process involving template switching.

中文翻译：

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端粒危机期间的染色体碎裂与 NHEJ 无关，并且与复制起源一致。

端粒侵蚀、功能障碍和融合可导致以大规模基因组不稳定为特征的细胞危机状态。我们通过对逃脱危机的细胞克隆群体进行全基因组序列分析，研究了端粒驱动的危机对基因组结构完整性的影响。大规模结构变异的量化揭示了与染色体碎裂一致的重排模式，但在缺乏功能性非同源末端连接通路的情况下形成。重排通常由具有复杂突变模式的短片段组成，其修复拓扑结构偏离随机性，显示优先修复局部区域或特定位点之间的交换。我们发现端粒参与富集折返倒转的证据，这些倒转倒转界定了重排簇。我们的数据表明，由端粒危机引起的染色体重排是通过涉及模板转换的复制修复过程产生的。