Numerical chromosomal instability mediates susceptibility to radiation treatment
Open accessAbstract
The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner. Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.
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Overexpression of Kif2b or MCAK directly suppresses CIN in otherwise chromosomally unstable cells.
“Destabilization of microtubule attachments to chromosomes at the kinetochores, through overexpression of the non-motile microtubule depolymerizing kinesin-13 proteins, Kif2b or MCAK/Kif2c, directly suppresses CIN in otherwise chromosomally unstable cells5–7.”
From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [6]
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- Authors
- Bakhoum, S. F., Kabeche, L., Wood, M. D., Laucius, C. D., Qu, D., Laughney, A. M., Reynolds, G. E., Louie, R. J., Phillips, J., Chan, D. A., Zaki, B. I., Murnane, J. P., Petritsch, C., & Compton, D. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Dartmouth College (US)
- University of California, San Francisco (US)
- Harvard University (US)
- Corresponding author
- Bakhoum, Samuel F.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-01-21
- Volume
- 6
- Issue
- 1
- Pages
- 5990-5990
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4516720
- OpenAlex
- W1968145208
- Cited by
- 95
- References
- 46
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 2
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Radiological Society of North America
- Dartmouth College
- Broad Institute
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute (R01CA120205, R01CA164746, P30CA023108, P01CA118816)
- National Institute of General Medical Sciences (R01GM008704, T32GM008704, R37GM051542)
- National Institute of Neurological Disorders and Stroke (R01NS080619)
- National Institute on Minority Health and Health Disparities (L60 MD001952)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- 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
- Keywords
- ionizing radiation, radioresistance (biology), aneuploidy, micronuclei, glioblastoma, fractionated radiotherapy, tumor cell viability
- MeSH terms
- Aneuploidy, Animals, Brain Neoplasms, Cell Cycle, Cell Survival, Glioblastoma, Humans, Male, Mice, Nude, Mitosis, Neoplasm Transplantation, Neoplasms, Radiation, Ionizing, Micronucleus Tests, Cell Death, Chromosome Breakage, Chromosome Segregation, Chromosomal Instability, HCT116 Cells, Cell Line, Tumor, Mice
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