Numerical chromosomal instability mediates susceptibility to radiation treatment

Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius, Dian Qu, Ashley M. Laughney, Gloria E. Reynolds, Raymond J. Louie, Joanna Phillips, Denise A. Chan, Bassem I. Zaki, John P. Murnane, Claudia Petritsch, Duane A. Compton

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number5990
JournalNature communications
Volume6
DOIs
StatePublished - Jan 21 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    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. (2015). Numerical chromosomal instability mediates susceptibility to radiation treatment. Nature communications, 6, [5990]. https://doi.org/10.1038/ncomms6990