DNA breaks and chromosome pulverization from errors in mitosis
Open accessAbstract
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.
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Telomeric erosion causing dicentric chromosome formation could lead to BFB and/or chromothripsis.
“raising the possibility that dicentric chromosome formation due to telomeric erosion could lead to BFB and/or chromothripsis [17, 18].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [17]
Defective nuclear envelope assembly in MN impairs replication and repair of MN DNA.
“which affects many processes in MN, including defective replication and repair of MN DNA (Crasta et al., 2012; Hatch et al., 2013; Umbreit et al., 2020; Zhang et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Crasta et al., 2012
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- Authors
- Crasta, K., Ganem, N. J., Dagher, R., Lantermann, A. B., Ivanova, E. V., Pan, Y., Nezi, L., Protopopov, A., Chowdhury, D., & Pellman, D.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pellman, David
- ORCID
- Venue
- Nature
- Published
- 2012-01-18
- Volume
- 482
- Issue
- 7383
- Pages
- 53-58
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3271137
- OpenAlex
- W2095617425
- Cited by
- 1,227
- References
- 52
- Citations by year
- 2026: 50 · 2025: 63 · 2024: 76 · 2023: 89 · 2022: 77 · 2021: 95 · 2020: 106 · 2019: 87 · 2018: 108 · 2017: 85 · 2016: 79 · 2015: 97 · 2014: 77 · 2013: 88 · 2012: 49
- FWCI
- 47.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R00CA154531, R01CA142698)
- National Institute of General Medical Sciences (GM 083299, R01GM083299)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- micronuclei, whole-chromosome aneuploidy, chromothripsis, DNA strand breaks, chromosome pulverization, lagging chromosomes, DNA damage response, chromosome fragmentation, carcinogenesis, chromosomal rearrangements, S phase
- MeSH terms
- Aneuploidy, Cell Transformation, Neoplastic, DNA Replication, Humans, Mitosis, Neoplasms, Chromosome Breakage, Chromosome Segregation, Comet Assay, Cell Line, Tumor, Micronuclei, Chromosome-Defective, DNA Fragmentation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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