When cells progress to malignancy, they must overcome a final telomere-mediated proliferative lifespan barrier called replicative crisis. Crisis is characterized by extensive telomere fusion that drives widespread genomic instability, mitotic arrest, hyperactivation of autophagy, and cell death. Recently, it has become apparent that that the resolution of dicentric chromosomes, which arise from telomere fusions during crisis, can initiate a sequence of events that leads to chromothripsis, a form of extreme genomic catastrophe. Chromothripsis is characterized by localized genomic regions containing tens to thousands of rearrangements and it is becoming increasingly apparent that chromothripsis occurs widely across tumor types and has a clinical impact. Here we discuss how telomere dysfunction can initiate genomic complexity and the emerging mechanisms of chromothripsis.

中文翻译：

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灾难性的结局：端粒驱动的基因组不稳定性的新兴机制。


当细胞进展为恶性肿瘤时，它们必须克服最终的端粒介导的增殖寿命障碍，称为复制危机。危机的特点是广泛的端粒融合，导致广泛的基因组不稳定、有丝分裂停滞、自噬过度激活和细胞死亡。最近，很明显，危机期间由端粒融合引起的双着丝粒染色体的解析可以引发一系列事件，导致染色体碎裂，这是一种极端的基因组灾难。染色体碎裂的特征是包含数万个重排的局部基因组区域，并且越来越明显的是，染色体碎裂广泛发生在各种肿瘤类型中并具有临床影响。在这里，我们讨论端粒功能障碍如何引发基因组复杂性以及染色体碎裂的新兴机制。