A storm of mutagenesis generates complexity in the cancer genome from a single cell division error. The interphase actomyosin cytoskeleton (green fibers) stretches and breaks chromosome bridges, promoting local chromosome fragmentation (damaged DNA indicated in red). Defective DNA replication, first during interphase and then in subsequent mitosis, leads to additional DNA damage and chromothripsis, in some cases leaving behind a specific mutational signature (TST jumps). Bridging chromosomes frequently disaggregate and form micronuclei, promoting further chromothripsis. Credit: Science (2020). DOI: 10.1126/science.aba0712
A team of researchers affiliated with multiple institutions in the US and UK found that a single mistake during cell division can trigger a cascade of mutational events, generating many of the features found in cancer genomes. . In their paper published in the journal Science, the group describes the use of live-cell imaging and single-cell whole-genome sequencing to study the impact of single-cell mutational events on subsequent cell development. Jacob Paiano and Andr Nussenzweig of the National Cancer Institute at the National Institutes of Health published a Perspective article in the same issue of the journal that describes some of the recent history behind chromothripsis research and the work done by researchers. researchers with this new effort.
For the past few generations, medical researchers have assumed that the complexity of the genomes of many cancerous tumors arises gradually. Small mutations during replication that add up over several generations can result in a large mix of errors. More recently, researchers discovered that cancer genomes can evolve faster than previously thought due to a single catastrophic mutation. They also discovered that the type of mutations seen in tumors can occur rapidly due to a wide variety of processes, most particularly those that occur during the chromosome break-melt-bridge cycle and chromothripsis (a process in which thousands of chromosomal rearrangements due to a single event). In this new effort, the researchers sought to find out if the different processes that lead to such tumors might be related.
To find out more, the team used an approach involving live cell imaging and single cell analysis. Whole Genome Sequencing: This technique allowed them to trace both the cellular and genetic repercussions that occurred after the generation of the chromatin bridge that connected the daughter cells. They found that a single dicentric chromosome fusion event could trigger a cascade of mutations in subsequent divisions of daughter cells, which could lead to instability in the genome and mutational heterogeneity in the genes of the cells that followed. This finding provides insight into the etiology of cancer, which could lead to further research to prevent mutations associated with chromothripsis.
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‘Chromosome Destruction’: Understanding Chromothripsis in Human Cancer More information: Neil T. Umbreit et al. Mechanisms generating cancer genome complexity from a single cell division error, Science (2020). DOI: 10.1126/science.aba0712 Magazine information: Science
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