Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction. Chromothripsis is a catastrophic event in which one or a few chromosomes are shattered and stitched back together in random order, producing a derivative chromosome with complex rearrangements within a few cell cycles. Chromosome mis-segregation during cell division frequently produces small nuclear structures called micronuclei, which are prone to irreversible nuclear envelope disruption during interphase and impaired nucleocytoplasmic compartmentalization. Micronucleated chromosomes accumulate extensive DNA damage and are susceptible to shattering during the next mitosis, generating multiple, distinct DNA fragments. Chromosome fragments are reassembled by DNA double-strand break repair to form a derivative chromosome. Chromatin bridges trapped between daughter cells are attacked by a cytoplasmic nuclease (three-prime repair exonuclease 1; TREX1) during interphase to generate DNA breaks and focal chromothripsis.