Letter | Published:

Cell death during crisis is mediated by mitotic telomere deprotection

Nature volume 522, pages 492496 (25 June 2015) | Download Citation

Abstract

Tumour formation is blocked by two barriers: replicative senescence and crisis1. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown2 increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.

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Acknowledgements

All data are archived at the Salk Institute. We thank the Salk Institute's J. Fitzpatrick of the Waitt Advanced Biophotonics Center and members of GT3 Core, C. O’Shea, G. Wahl, F. Zhang, and D. Sabatini for support and Karlseder laboratory members for comments. M.T.H. was supported by the Human Frontier Science Program and the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad. A.J.C. was supported by a NIH NRSA T32 Fellowship (5T32CA009370). T.R. was supported by the Glenn Center for Research on Aging and CIRM training grant TG2-01158. The Salk Institute Cancer Center Core Grant (P30CA014195), the NIH (R01GM087476, R01CA174942), the Donald and Darlene Shiley Chair, the Highland Street Foundation, the Fritz B. Burns Foundation, the Emerald Foundation and the Glenn Center for Research on Aging support J.K.

Author information

Affiliations

  1. The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 North Torrey Pines Road, La Jolla, California 92037, USA

    • Makoto T. Hayashi
    • , Anthony J. Cesare
    • , Teresa Rivera
    •  & Jan Karlseder
  2. Department of Gene Mechanisms, Graduate School of Biostudies/The Hakubi Center for Advanced Research, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

    • Makoto T. Hayashi
  3. Children's Medical Research Institute, University of Sydney, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia

    • Anthony J. Cesare

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Contributions

M.T.H. and A.J.C. designed and performed experiments, and wrote the manuscript, T.R. performed experiments, J.K. designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan Karlseder.

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DOI

https://doi.org/10.1038/nature14513

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