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Cited by 745Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysMicrotubule and mitosis dynamics

Telomeres in cancer: tumour suppression and genome instability

Open access
Maciejowski, John, de Lange, Titia·2017·Nature Reviews Molecular Cell Biology
DOI 10.1038/nrm.2016.171PMC PMC5589191
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Abstract

The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.

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Crossref · 10.1038/nrm.2016.171

Cites

185 of 185 references verified0 citation errors · 0 not checkable

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Claims the paper makes

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  • Interpretationnone given

    Telomere shortening can suppress tumours by inducing proliferation arrest through ATM and ATR activation at unprotected chromosome ends.

    “On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Loss of telomere function at a few chromosome ends is sufficient to induce replicative arrest.

    “Loss of telomere function at a few chromosome ends in a cell is sufficient to induce replicative arrest9,39,40 (FIG. 2b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Davoli, T. & de Lange, T. Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell 21, 765–776 (2012). Reports that telomere-driven tetraploidy occurs in human cells during telomere crisis. source

      Not checked in the free run.

    • cites [39] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). Finds that telomeres in senescent cells exhibit the hallmarks of DNA DSBs. source

      Not checked in the free run.

    • cites [40] Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W. & Wright, W. E. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol. Biol. Cell 15, 3709–3718 (2004). source

      Not checked in the free run.

  • Interpretationnone given

    Loss of telomere protection can cause telomere crisis, a state of extensive genome instability that can promote cancer progression.

    “On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In human cells without telomerase, telomeres shorten by 50-100 base pairs per population doubling.

    “In the absence of telomerase, each human telomere shortens at a rate of 50–100 bps per population doubling29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). Demonstrates that the telomeres of human fibroblasts shorten during growth in culture. source

      Not checked in the free run.

  • Interpretationnone given

    Telomere crisis can induce cancer-relevant changes including chromothripsis, kataegis, and tetraploidization.

    “Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.”
    Quote in the paperSubstantial claim
  • May combine two claims. 20

  • May combine two claims.

    Premisecitation

    Telomerase activation and telomere-length maintenance allow bypass of senescence and lead to cell immortalization.

    “Telomerase activation and the resulting telomere-length maintenance leads to the bypass of senescence and ultimately to cell immortalization23,26,27.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). Establishes a causal relationship between telomere shortening and cellular senescence. source

      Not checked in the free run.

    • cites [26] Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15, 398–403 (2001). source

      Not checked in the free run.

    • cites [27] Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The programmed silencing of TERT, loss of telomerase activity, and telomere shortening is not universal in mammals; it appears restricted to large animals with long lifespan.

    “The programmed silencing of TERT, loss of telomerase activity and the resulting shortening of telomeres is not a universal phenomenon in mammals. Apparently, this tumour suppressor pathway is restricted to large animals with a reproductive strategy that requires a long lifespan28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Gomes, N. M. V. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREX1 creates extensive single-stranded DNA in chromatin bridges, leading to accumulation of RPA on the bridges.

    “The exonuclease creates extensive single-stranded DNA in chromatin bridges, leading to an accumulation of the single-stranded DNA-binding protein replication protein A (RPA) on the bridges (FIG. 5b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015). Shows that dicentric chromosomes formed during telomere crisis persist through mitosis, are fragmented by TREX1 in G1 phase and give rise to chromothripsis and kataegis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because increased telomere length is present at birth, POT1 mutations likely delay senescence and postpone the tumour-suppressive effects of telomere attrition to a point of irrelevance.

    “Because the increased telomere length is present at birth, these mutations are likely to push the onset of senescence to later population doublings, thus postponing the tumour-suppressive effects of telomere attrition to a point of irrelevance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomere fusions formed during telomere crisis in cultured cells are mediated by alt-NHEJ and show insertion of new sequences at the fusion point.

    “Telomere fusions formed during telomere crisis in cultured cells are mediated by alt-NHEJ and exhibit insertion of new sequences at the fusion point75,76.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Capper, R. et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 21, 2495–2508 (2007). source

      Not checked in the free run.

    • cites [76] Oh, S. et al. DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cells. DNA Repair 21, 97–110 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kataegis is found at the breakpoints of chromothriptic rearrangements created by telomere crisis, consistent with APOBEC activity.

    “Consistent with APOBEC activity, kataegis is found at the breakpoints of chromothriptic rearrangements created by telomere crisis3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015). Shows that dicentric chromosomes formed during telomere crisis persist through mitosis, are fragmented by TREX1 in G1 phase and give rise to chromothripsis and kataegis. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Cells in telomere crisis have end-to-end fused dicentric chromosomes, which cause mitotic mis-segregation and genomic instability.

    “Consequently, cells in telomere crisis have end-to-end fused dicentric chromosomes, which lead to mitotic mis-segregation and genomic instability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Tissues expressing ETS transcription factors are predicted to maintain telomerase activity and telomere length, disrupting the telomere tumour suppressor pathway.

    “Thus, tissues that express ETS transcription factors are predicted to maintain telomerase activity, presumably resulting in the maintenance of telomere length and the consequent disruption of the telomere tumour suppressor pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013). Identifies activating mutations in the TERT promoter through an analysis of melanoma-prone families. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dicentric chromosomes persist through mitosis and form long chromatin bridges that connect daughter cells into the next G1 phase.

    “These dicentric chromosomes invariably persist through mitosis and form long chromatin bridges that connect the daughter cells well into the next G1 phase3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015). Shows that dicentric chromosomes formed during telomere crisis persist through mitosis, are fragmented by TREX1 in G1 phase and give rise to chromothripsis and kataegis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of shelterin activates DNA damage signalling, upregulates p21 and p16, and causes DDR factors to accumulate at telomeres, linking telomere dysfunction to senescence.

    “The inactivation of shelterin similarly activates DNA damage signalling pathways, results in the upregulation of p21 and p16, and leads to the accumulation of DDR factors at telomeres, thus linking telomere dysfunction and senescence39,42.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). Finds that telomeres in senescent cells exhibit the hallmarks of DNA DSBs. source

      Not checked in the free run.

    • cites [42] Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Carriers of POT1 mutations have longer telomeres, likely because POT1-mediated inhibition of telomerase is lost.

    “Carriers of these mutations have longer telomeres, presumably owing to the loss of POT1-mediated inhibition of telomerase (BOX 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Robles-Espinoza, C. D. et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 46, 478–481 (2014). Links germline, loss-of-function variants of POT1 to melanoma susceptibility and increased telomere length. source

      Not checked in the free run.

    • cites [63] Shi, J. et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 46, 482–486 (2014). Reports the identification of unrelated, melanoma-prone families that carry variants of POT1 and show increased telomere lengths. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 95,568 individuals from the general population, genetic determinants of long telomeres are associated with increased overall cancer risk, especially lung cancer and melanoma.

    “This analysis found that genetic determinants of long telomeres are associated with an increased overall cancer risk, especially lung cancer and melanoma.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Rode, L., Nordestgaard, B. G. & Bojesen, S. E. Long telomeres and cancer risk among 95 568 individuals from the general population. Int. J. Epidemiol. 45, 1634–1643 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Overexpression of TRF2 can delay senescence, indicating that the DDR in senescence results from insufficient shelterin loading at shortened telomeres.

    “Furthermore, over-expression of the shelterin subunit telomeric repeat-binding factor 2 (TRF2; also known as TERF2) can delay the onset of senescence44, arguing that the DDR in senescence is due to an insufficient loading of shelterin at the shortened telomeres.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Karlseder, J., Smogorzewska, A. & de Lange, T. Senescence induced by altered telomere state, not telomere loss. Science 295, 2446–2449 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Telomerase reactivation provides a route out of telomere crisis, stabilizing the genome and rescuing cellular fitness.

    “Ultimately, telomerase reactivation provides a route out of telomere crisis, stabilizing the genome and rescuing cellular fitness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TERT promoter mutations are the most common non-coding mutations in cancer and are found in a growing list of cancers.

    “These mutations are the most common mutations in non-coding sequences in cancer and are found in a long, and almost certainly growing, list of cancers153–158.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [153] Heidenreich, B., Rachakonda, P. S., Hemminki, K. & Kumar, R. TERT promoter mutations in cancer development. Curr. Opin. Genet. Dev. 24, 30–37 (2014). source

      Not checked in the free run.

    • cites [154] Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6026 (2013). source

      Not checked in the free run.

    • cites [155] Kinde, I. et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 73, 7162–7167 (2013). source

      Not checked in the free run.

    • cites [156] Remke, M. et al. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol. 126, 917–929 (2013). source

      Not checked in the free run.

    • cites [157] Quaas, A. et al. Frequency of TERT promoter mutations in primary tumors of the liver. Virchows Arch. 465, 673–677 (2014). source

      Not checked in the free run.

    • cites [158] Weinhold, N., Jacobsen, A., Schultz, N., Sander, C. & Lee, W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat. Genet. 46, 1160–1165 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In urothelial cancers, TERT promoter mutations correlate with higher TERT mRNA and protein levels, enzymatic activity, and greater telomere length.

    “An analysis of these mutations in urothelial cancers showed that they are correlated with higher levels of TERT mRNA and protein levels and enzymatic activity and with greater telomere length159.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Borah, S. et al. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347, 1006–1010 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In colorectal cancer, telomere fusion occurs during the adenoma-carcinoma transition and may also be present before most somatic mutations.

    “In colorectal cancer, telomere fusion occurs during the adenoma–carcinoma transition and may also be present before the occurrence of most somatic mutations78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Jones, R. E. et al. Escape from telomere-driven crisis is DNA ligase III dependent. Cell Rep. 8, 1063–1076 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mechanism of tetraploidization involves persistent ATM/ATR signalling from irreparably damaged telomeres, prolonged G2, bypass of mitosis, entry into a G1-like state, and a second S phase causing whole-genome reduplication.

    “The mechanism of tetraploidization involves persistent ATM-dependent and/or ATR-dependent signalling induced by irreparably damaged telomeres. This signalling leads to a prolonged G2 phase and ultimately a bypass of mitosis and entry into a G1-like state. A second S phase then results in whole-genome reduplication and tetraploidy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mouse models, continued telomere dysfunction can constrain cancer progression, whereas telomerase reactivation alleviates intratumoural DNA damage and leads to more aggressive tumour progression and metastasis.

    “In mouse models, continued telomere dysfunction can constrain cancer progression, whereas telomerase reactivation alleviates intratumoural DNA damage and leads to more aggressive tumour progression and metastasis168.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Ding, Z. et al. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148, 896–907 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TERT promoter mutations are usually mutually exclusive with ATRX mutations, supporting the notion that ALT provides a telomerase-independent escape from telomere crisis.

    “The observations that TERT promoter mutations are usually mutually exclusive with mutations in ATRX support the notion that ALT may provide a telomerase-independent escape from telomere crisis166,167.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [166] Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016). source

      Not checked in the free run.

    • cites [167] Eckel-Passow, J. E. et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N. Engl. J. Med. 372, 2499–2508 (2015). source

      Not checked in the free run.

20 of 20

  • The authors state this as an assumption.

    The loss of viability in telomere crisis is driven by chromosome breakage and mis-segregation.

    “A common assumption is that this loss of viability is driven by chromosome breakage and mis-segregation, although it may also involve additional telomere deprotection during an extended mitotic arrest that occurs in some of the cells71,72.”

  • The authors state this as an assumption.

    Repair of the fragmented dicentric chromosome occurs during the cell cycle in which the RPA mark dissipates.

    “As the RPA mark usually dissipates within one cell cycle, repair of the fragmented dicentric chromosome is presumed to occur during this period3.”

  • The paper relies on this without support.

    Most mutations are deleterious to cellular fitness.

    “However, persistence of a mutator phenotype comes at a cost because most mutations are deleterious to cellular fitness.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Telomerase is described as both required and optional for escape from crisis

    Minor

    The paper says escape from telomere crisis requires telomerase activation, but later describes ALT as a telomerase-independent route out of the same crisis.

1 of 1

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Authors
Maciejowski, J., & de Lange, T.
Affiliations
Rockefeller University (US)
ORCID
Maciejowski, John
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2017-01-18
Volume
18
Issue
3
Pages
175-186
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/nrm.2016.171
PMC
PMC5589191
OpenAlex
W2577194681
Cited by
745
References
185
Citations by year
2026: 45 · 2025: 84 · 2024: 107 · 2023: 68 · 2022: 79 · 2021: 101 · 2020: 94 · 2019: 60 · 2018: 75 · 2017: 30 · 2015: 1
FWCI
8.69
Type
journal article
Language
en
Update notices
correction (2019-02-28)
Open access
Licence
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R56AG016642, R01AG016642)
  • National Cancer Institute (R01CA181090, K99CA212290, R00CA212290)
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
telomeres, telomere shortening, telomere crisis, tumor suppression, genomic instability, chromothripsis, kataegis, tetraploidization, ATM kinase, ATR kinase, proliferation arrest, chromosomal rearrangements, carcinogenesis
MeSH terms
Chromothripsis, Humans, Neoplasms, Telomere, Telomerase, Genomic Instability, Telomere Shortening

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