Cell
Volume 163, Issue 7, 17 December 2015, Pages 1641-1654
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Article
Chromothripsis and Kataegis Induced by Telomere Crisis

https://doi.org/10.1016/j.cell.2015.11.054Get rights and content
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Highlights

  • Dicentric chromosomes formed during telomere crisis do not break in mitosis

  • Cells with dicentrics develop chromatin bridges that induce nuclear envelope rupture

  • The TREX1 3′ nuclease generates ssDNA in the bridges and facilitates their resolution

  • Post-telomere crisis cells often show chromothripsis and kataegis

Summary

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 hr 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.

Keywords

telomere crisis
chromothripsis
kataegis
NERDI
TREX1
APOBEC
dicentric chromosome

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