Chromothripsis and kataegis induced by telomere crisis

By J. Maciejowski, Yilong Li, Nazario Bosco, Peter J. Campbell, T. de Lange. Cell, 2015

616 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b0946ce2c854c14e5087ddc063e8cf851f5e1069

Citations in the corpus

• Patterns of somatic structural variation in human cancer genomes (2020, neutral): “Although chromothripsis with copy number gain has been described 3,11,19,22 , the resulting copy number and rearrangement patterns have different properties to those described here.”