title: DNA breaks and chromosome pulverization from errors in mitosis.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Crasta
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ganem
authors.forename: Regina
authors.initials: R
authors.lastname: Dagher
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Lantermann
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ivanova
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Pan
authors.forename: Luigi
authors.initials: L
authors.lastname: Nezi
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: David
authors.initials: D
authors.lastname: Pellman
mesh_terms: D000782:Aneuploidy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019457:Chromosome Breakage; D020090:Chromosome Segregation; D020552:Comet Assay; D053938:DNA Fragmentation; D004261:DNA Replication; D006801:Humans; D048629:Micronuclei, Chromosome-Defective; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology