The study investigates the mechanism of chromothripsis, a mutational phenomenon characterized by extensive genomic rearrangements and oscillating DNA copy number levels, restricted to one or a few chromosomes. The authors propose that chromothripsis can occur through the physical isolation of chromosomes in micronuclei, which are aberrant nuclear structures formed during cell division errors. Using live-cell imaging and single-cell genome sequencing, they demonstrate that micronucleus formation can generate a spectrum of genomic rearrangements, including those that recapitulate all known features of chromothripsis. These events are restricted to the missegregated chromosome and occur within one cell division. The mechanism involves the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. The findings establish a new mutational process where chromothripsis is one extreme outcome. The study also highlights the critical importance of nuclear architecture and nuclear envelope integrity for genome stability and suggests that mitotic chromosome segregation errors can be heavily mutagenic, potentially contributing to cancer and other human diseases.The study investigates the mechanism of chromothripsis, a mutational phenomenon characterized by extensive genomic rearrangements and oscillating DNA copy number levels, restricted to one or a few chromosomes. The authors propose that chromothripsis can occur through the physical isolation of chromosomes in micronuclei, which are aberrant nuclear structures formed during cell division errors. Using live-cell imaging and single-cell genome sequencing, they demonstrate that micronucleus formation can generate a spectrum of genomic rearrangements, including those that recapitulate all known features of chromothripsis. These events are restricted to the missegregated chromosome and occur within one cell division. The mechanism involves the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. The findings establish a new mutational process where chromothripsis is one extreme outcome. The study also highlights the critical importance of nuclear architecture and nuclear envelope integrity for genome stability and suggests that mitotic chromosome segregation errors can be heavily mutagenic, potentially contributing to cancer and other human diseases.