Nature, 2015 June 11; 522(7555): 179–184. doi:10.1038/nature14493. Chromothripsis is a rare genomic phenomenon characterized by extensive rearrangements and oscillating DNA copy number levels, confined to one or a few chromosomes. This study demonstrates that chromothripsis can occur through the fragmentation and reassembly of a single chromatid from a micronucleus, which forms when chromosomes are missegregated during cell division. Micronuclei are often formed due to errors in cell division or DNA repair, and their rupture during S phase leads to DNA damage that can be repaired in the daughter nuclei, resulting in chromosomal rearrangements. The study used live-cell imaging and single-cell genome sequencing to show that micronuclei can generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the missegregated chromosome and occur within one cell division. The research also identified that chromothripsis involves the fragmentation of a single chromatid from a micronucleus, followed by random reassembly. The study found that DNA damage in micronuclei is not triggered by nuclear envelope rupture alone but also requires entry into S phase. Micronuclei from serum-starved G0 cells showed little DNA damage despite envelope rupture, indicating that DNA damage is not solely due to rupture. The results suggest that DNA damage in micronuclei is associated with the initiation of DNA replication. The study developed a method called "Look-Seq" to determine the genomic consequences of DNA damage in ruptured micronuclei. This method involved sorting cells, isolating daughter cells, and analyzing their genomes. The results showed that chromosomes in micronuclei are underreplicated and that DNA damage is concentrated on the missegregated chromosome. The study identified that chromothripsis involves localized chromosome rearrangements, with a concentration of rearrangements on the missegregated chromosome. These rearrangements were associated with the "gained" or "missegregated" haplotype. The study also found that chromothripsis can generate double minute chromosomes, which are small circular acentric chromosomes that can carry oncogenes. The study provides evidence that chromothripsis can occur through the fragmentation and reassembly of a single chromatid from a micronucleus. This process can lead to extensive mutagenesis and is a significant source of genetic variation. The findings highlight the importance of nuclear architecture and nuclear envelope integrity for genome stability in eukaryotic cells. The study also suggests that chromothripsis may originate from DNA replication errors that generate microhomology-mediated break-induced replication (MMBIR). The results indicate that chromothripsis is a significant mutational process that can contribute to cancer and other human diseases.Nature, 2015 June 11; 522(7555): 179–184. doi:10.1038/nature14493. Chromothripsis is a rare genomic phenomenon characterized by extensive rearrangements and oscillating DNA copy number levels, confined to one or a few chromosomes. This study demonstrates that chromothripsis can occur through the fragmentation and reassembly of a single chromatid from a micronucleus, which forms when chromosomes are missegregated during cell division. Micronuclei are often formed due to errors in cell division or DNA repair, and their rupture during S phase leads to DNA damage that can be repaired in the daughter nuclei, resulting in chromosomal rearrangements. The study used live-cell imaging and single-cell genome sequencing to show that micronuclei can generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the missegregated chromosome and occur within one cell division. The research also identified that chromothripsis involves the fragmentation of a single chromatid from a micronucleus, followed by random reassembly. The study found that DNA damage in micronuclei is not triggered by nuclear envelope rupture alone but also requires entry into S phase. Micronuclei from serum-starved G0 cells showed little DNA damage despite envelope rupture, indicating that DNA damage is not solely due to rupture. The results suggest that DNA damage in micronuclei is associated with the initiation of DNA replication. The study developed a method called "Look-Seq" to determine the genomic consequences of DNA damage in ruptured micronuclei. This method involved sorting cells, isolating daughter cells, and analyzing their genomes. The results showed that chromosomes in micronuclei are underreplicated and that DNA damage is concentrated on the missegregated chromosome. The study identified that chromothripsis involves localized chromosome rearrangements, with a concentration of rearrangements on the missegregated chromosome. These rearrangements were associated with the "gained" or "missegregated" haplotype. The study also found that chromothripsis can generate double minute chromosomes, which are small circular acentric chromosomes that can carry oncogenes. The study provides evidence that chromothripsis can occur through the fragmentation and reassembly of a single chromatid from a micronucleus. This process can lead to extensive mutagenesis and is a significant source of genetic variation. The findings highlight the importance of nuclear architecture and nuclear envelope integrity for genome stability in eukaryotic cells. The study also suggests that chromothripsis may originate from DNA replication errors that generate microhomology-mediated break-induced replication (MMBIR). The results indicate that chromothripsis is a significant mutational process that can contribute to cancer and other human diseases.