Format

Send to

Choose Destination
See comment in PubMed Commons below
Nature. 2015 Jun 25;522(7557):492-6. doi: 10.1038/nature14513.

Cell death during crisis is mediated by mitotic telomere deprotection.

Author information

1
1] The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 North Torrey Pines Road, La Jolla, California 92037, USA [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.
2
1] The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 North Torrey Pines Road, La Jolla, California 92037, USA [2] Children's Medical Research Institute, University of Sydney, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia.
3
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

Abstract

Tumour formation is blocked by two barriers: replicative senescence and crisis. 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) knockdown 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.

PMID:
26108857
PMCID:
PMC4481881
DOI:
10.1038/nature14513
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center