Cell death during crisis is mediated by mitotic telomere deprotection
Open accessAbstract
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.
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Fused chromosomes can initiate bridge-breakage-fusion cycles, causing more chromosome rearrangements and genomic instability that promote mitotic crisis.
“These fused chromosomes can initiate bridge–breakage–fusion cycles, causing more chromosome rearrangements and genomic instability that promote mitotic crisis [349,350].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [350]
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- Authors
- Hayashi, M. T., Cesare, A. J., Rivera, T., & Karlseder, J.
- Affiliations
- Salk Institute for Biological Studies (US)
- The University of Sydney (AU)
- Corresponding author
- Karlseder, Jan
- Venue
- Nature
- Published
- 2015-06
- Volume
- 522
- Issue
- 7557
- Pages
- 492-496
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4481881
- OpenAlex
- W1899376386
- Cited by
- 125
- References
- 30
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 11 · 2023: 7 · 2022: 6 · 2021: 17 · 2020: 15 · 2019: 11 · 2018: 15 · 2017: 12 · 2016: 9 · 2015: 5
- FWCI
- 10.07
- 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
- National Cancer Institute (R01CA174942, T32CA009370, P30CA014195)
- National Institute of General Medical Sciences (R01GM087476)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- replicative senescence, crisis, telomere fusion, mitotic arrest, p53, telomerase, TRF2, DNA damage response, cell death, mitotic poisons, genomic instability, carcinogenesis, precancerous cells
- MeSH terms
- Cell Line, Chromosome Aberrations, Chromosomes, Human, DNA Damage, Humans, Mitosis, Neoplasms, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Cell Death, Telomerase, Telomeric Repeat Binding Protein 2, Genomic Instability, Gene Fusion, Cell Cycle Checkpoints
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