Chromothripsis from DNA damage in ... | Article | H1 Connect

This paper investigates a curious mutational phenomenon called chromothripsis in which thousands of rearrangement events occur in confined genomic regions. The authors perform a series of imaging experiments and single-cell sequencing to support their hypothesis that chromothripsis occurs as a result of the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. In addition to shedding light on the phenomenon of chromothripsis, this paper describes means to manipulate a potentially very powerful model system for genetic research.

Chromothripsis is a type of genetic aberration displayed as fragmentation of DNA and subsequent aberrant stitching of the DNA-fragments, usually within one chromosome {1}. It has been identified in several cancer types, with the highest frequency in bone cancer. The mechanism how chromothripsis occurs is not elucidated, but in this paper, the authors provide a plausible explanation, which is supported by thoughtful experiments. They hypothesise that chromothripsis occurs in micronuclei. These are aberrant chromosomal structures that fail to attach to the mitotic spindle, thereby giving rise to acentric chromosomes and mis-segregation of chromosomes during mitosis. When these structures are reincorporated into the daughter cell after mitosis, this may result in chromothripsis. By a technology that they name ‘Look-Seq’, they first do a single-cell genomic live imaging and focus on micronuclei that rupture after S-phase due to nuclear envelope collapse. This results in under-replication of the micronucleus chromosome. The cells with and without micronuclei subsequently undergo single-cell sequencing and thus under-replicated DNA is identified as the micronuclei chromosome. Circos plots of the mis-segregated chromosomes show extensive long-range intrachromosomal rearrangements, like those detected in chromothripsis. Also interchromosomal rearrangements and double minutes are found. The authors show that de novo chromothripsis in their system is an all-at-once catastrophe, and their results suggest that micronuclei are the starting point for this event.