Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes^1,2,3,4,5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes⁴, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage–fusion–bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.

Chromothripsis 和 kataegis 经常在癌症中观察到，可能由端粒危机引起，端粒危机是肿瘤发生过程中基因组不稳定的时期，此时端粒储备的耗尽会产生不稳定的双着丝粒染色体^1,2,3,4,5。在这里，我们通过使用体外端粒危机模型来研究染色体碎裂和卡塔吉斯的潜在机制。^{我们发现细胞质核酸外切酶 TREX1 可促进双着丝粒染色体4}的解析，在染色体碎裂中发挥着重要作用。在缺乏TREX1的情况下，端粒危机引起的基因组改变主要涉及断裂-融合-桥循环和简单的基因组重排，而不是染色体碎裂。此外，我们表明在染色体碎裂断点处观察到的 kataegis 是 APOBEC3B 胞嘧啶脱氨基的结果。这些数据表明，chromothripsis 和 kataegis 是由 TREX1 的溶核处理和 APOBEC3B 的胞嘧啶编辑相结合产生的。