Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy
Open accessAbstract
Tetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these cells have an extended G2 due to ATM/ATR- and Chk1/Chk2-mediated inhibition of Cdk1/CyclinB and eventually bypass mitosis. Despite their lack of mitosis, the cells showed APC/Cdh1-dependent degradation of the replication inhibitor geminin, followed by accumulation of Cdt1, which is required for origin licensing. Cells then entered a second S phase resulting in whole-genome reduplication and tetraploidy. Upon restoration of telomere protection, these tetraploid cells resumed cell division cycles and proliferated. These observations suggest a general mechanism for the induction of tetraploidization in the early stages of tumorigenesis when telomere dysfunction can result from excessive telomere shortening.
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The repertoire of genomic alterations attributable to telomere crisis is more extensive and includes whole-genome reduplication, chromothripsis, and kataegis.
“However, it has recently become clear that the repertoire of genomic alterations that can be ascribed to telomere crisis is more extensive and includes whole-genome reduplication, chromothripsis and kataegis3,8,9.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [8]
Telomere crisis can induce tetraploidization.
“Finally, telomere crisis can induce tetraploidization (doubling the set of chromosomes)8,9, which is inferred to be a frequent event during the development of human cancers125.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [8]
Tetraploidization can be induced in cells lacking p53 and RB pathways that have a high load of dysfunctional telomeres.
“Tetraploidization can be induced in cells that lack the p53 and RB pathways, which have a high load of dysfunctional telomeres8,9 (FIG. 6).”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [8]
In p53/pRb-deficient MEFs, persistent telomere dysfunction causes prolonged G2 arrest and genome reduplication/tetraploidy because the p53/p21-dependent G1/S checkpoint is absent.
“Conversely, in p53/pRb-deficient MEFs, DNA damage generated by persistent telomere dysfunction induces prolonged G2 arrest that leads to genome reduplication and tetraploidy due to the absence of the p53/p21-dependent G1/S checkpoint (Fig. 3; 88 ).”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
Strong persistent DNA damage signaling from POT1a/b double knockdown likely causes sustained Chk1/2 activation that prevents Cdk1 activation and mitosis, producing prolonged G2 arrest that enables mitotic bypass and a new replication round.
“The most likely explanation is that the strong and persistent DNA damage signaling induced by POT1a/b double knockdown 88 causes sustained Chk1/2 activation that prevents Cdk1 activation (and mitosis), resulting in prolonged G2 arrest.This would enable the mitotic bypass and the onset of a new round of replication (Fig. 3).”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
Mitotic bypass requires p53; its absence leads to aberrant mitosis and cell death.
“The results showing that mitotic bypass requires p53, as its absence leads to aberrant mitosis and cell death, corroborate the observations by the Karlseder team, 83 but they apparently contradict the finding that mitotic bypass in p53-deficient cells leads to endoreplication.88”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
This stable G2 arrest causes endoreplication through mitotic bypass.
“In p53-deficient cells, in the case of persistent telomere dysfunction, DNA damage induces strong and sustained Chk1/2 activation leading to stable G2 arrest that, via mitotic bypass, leads to endoreplication, resulting in tetraploidy.88”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
This strong and sustained Chk1/2 activation leads to stable G2 arrest.
“In p53-deficient cells, in the case of persistent telomere dysfunction, DNA damage induces strong and sustained Chk1/2 activation leading to stable G2 arrest that, via mitotic bypass, leads to endoreplication, resulting in tetraploidy.88”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
Endoreplication results in tetraploidy.
“In p53-deficient cells, in the case of persistent telomere dysfunction, DNA damage induces strong and sustained Chk1/2 activation leading to stable G2 arrest that, via mitotic bypass, leads to endoreplication, resulting in tetraploidy.88”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
When p53 is missing and telomere dysfunction persists, DNA damage triggers robust, prolonged Chk1/2 activation.
“In p53-deficient cells, in the case of persistent telomere dysfunction, DNA damage induces strong and sustained Chk1/2 activation leading to stable G2 arrest that, via mitotic bypass, leads to endoreplication, resulting in tetraploidy.88”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [88]
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- Authors
- Davoli, T., Denchi, E. L., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 141
- Issue
- 1
- Pages
- 81-93
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2854042
- OpenAlex
- W2025088179
- Cited by
- 298
- References
- 53
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 19 · 2023: 16 · 2022: 9 · 2021: 14 · 2020: 17 · 2019: 8 · 2018: 23 · 2017: 20 · 2016: 24 · 2015: 25 · 2014: 17 · 2013: 28 · 2012: 33
- FWCI
- 19.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1203 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
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- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP1OD000379)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- tetraploidization, telomere dysfunction, telomere shortening, p53 deficiency, aneuploidy, carcinogenesis, G2 cell cycle arrest, ATM/ATR signaling, APC/Cdh1, Cdt1, telomere protection
- MeSH terms
- Aneuploidy, Animals, Cell Line, DNA Damage, Embryo, Mammalian, Humans, Mitosis, Neoplasms, Ploidies, Cadherins, Telomere, Cell Cycle Proteins, Ubiquitin-Protein Ligase Complexes, Mice, Anaphase-Promoting Complex-Cyclosome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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