DNA breaks and chromosome pulverization from errors in mitosis

Karen Crasta, Neil J. Ganem, Regina Dagher, Alexandra B. Lantermann, Elena V. Ivanova, Yunfeng Pan, Luigi Nezi, Alexei Protopopov, Dipanjan Chowdhury and David Pellman ()
Additional contact information
Karen Crasta: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Neil J. Ganem: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Regina Dagher: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Alexandra B. Lantermann: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Elena V. Ivanova: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, 4 Blackfan Street, Boston, Massachusetts 02115, USA
Yunfeng Pan: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Luigi Nezi: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
Alexei Protopopov: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, 4 Blackfan Street, Boston, Massachusetts 02115, USA
Dipanjan Chowdhury: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA
David Pellman: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA

Nature, 2012, vol. 482, issue 7383, 53-58

Abstract: Abstract The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for ‘chromothripsis’ in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.

Date: 2012
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DOI: 10.1038/nature10802

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