DNA breaks and chromosome pulverization from errors in mitosis

• Published in: Nature (London) Vol. 482; no. 7383; pp. 53 - 58
• Main Authors: Crasta, Karen, Ganem, Neil J., Dagher, Regina, Lantermann, Alexandra B., Ivanova, Elena V., Pan, Yunfeng, Nezi, Luigi, Protopopov, Alexei, Chowdhury, Dipanjan, Pellman, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2012; Nature Publishing Group
• Subjects: 631/337/1427; 631/67; 631/80/641/1655; 692/420/2489/1381; Aneuploidy; Artificial chromosomes; Biological and medical sciences; Cancer; Causes of; Cell cycle; Cell cycle, cell proliferation; Cell Line, Tumor; Cell physiology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Chromosome Breakage; Chromosome Segregation; Comet Assay; Deoxyribonucleic acid; DNA; DNA damage; DNA Fragmentation; DNA Replication; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genomes; Health aspects; Humanities and Social Sciences; Humans; Methods; Micronuclei, Chromosome-Defective; Mitosis; Mitosis - genetics; Molecular and cellular biology; multidisciplinary; Neoplasms - etiology; Neoplasms - genetics; Neoplasms - pathology; Science; Science (multidisciplinary); United States; Error; Chromosome break; Mitosis; DNA; Cell cycle
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10802

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. Chromosomes within micronuclei are shown to be damaged during S phase and become highly fragmented, and the damaged pieces can be reincorporated into the genome. Small fragments, devastating effects It is well established that DNA breaks can cause cancers. Less clear, and the subject of debate for many years, is the question of whether whole-chromosome aneuploidy, in which a cell's chromosome number is not a multiple of the haploid number, also contributes to tumorigenesis. This paper identifies a mechanism by which whole-chromosome segregation errors can cause chromosome breaks and potentially cancer-causing mutations. Using a system that produces lagging chromosomes to generate micronuclei, Crasta et al . find that chromosomes within the micronuclei become damaged during S phase, owing to abnormal replication and an impaired DNA damage response. These chromosomes become highly fragmented, and the broken, damaged pieces can be reincorporated into the main genome during mitosis, causing various DNA lesions. This work also suggests a mechanism that might explain the recently discovered phenomenon of chromothripsis, in which fragmented chromosomes acquire multiple cancer-causing mutations in a single event as a result of their imperfect reassembly.