Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation
Open accessAbstract
The DNA-damage response (DDR) arrests cell-cycle progression until damage is removed. DNA-damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.
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Ageing is consistently associated with increased DNA damage response in proliferating and non-proliferating cells, contributing to senescent cell accumulation with age.
“Ageing is one of the factors that is consistently associated with an increase in DDR in proliferating and non-proliferating cells, thus contributing significantly to the accumulation of senescent cells with age35,89”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [35]
The Abstract reports more DDR-positive cells with age across tissues and cell types, and the Results section on physiological ageing in primates reports persistent DDR foci in non-dividing neurons and hepatocytes. The Discussion proposes that persistent telomeric DDR leads to senescence, but does not establish that increased DDR contributes significantly to the accumulation of senescent cells with age. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAged mouse hepatocytes show senescence-associated markers including SA-β-gal activity, TAF, karyomegaly, SADS, LINE-1 expression and SASP factors.
“Studies on aged mouse hepatocytes have shown the presence of senescence-associated markers such as SA-β-gal activity157, TAF54,158, karyomegaly and SADS159, LINE-1 expression23 and expression of SASP factors141.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [158]
The Results section on physiological ageing in primates reports telomere-associated DNA-damage foci in liver hepatocytes from old baboons, supporting the TAF portion of the citation. It does not establish TAF in aged mouse hepatocytes; its mouse experiment examined irradiated hippocampal neurons. The other listed markers have separate citations and are not attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDysfunctional telomeres trigger a DNA damage response but block attempted DNA repair.
“Dysfunctional telomeres elicit a DNA damage response (DDR) but suppress attempted DNA repair (22–25).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [24]
Dysfunctional telomeres appear irreparable, so cells with them have persistent DDR signaling and p53 activation that enforce senescence arrest.
“Dysfunctional telomeres appear to be irreparable; consequently, cells with such telomeres experience persistent DDR signaling and p53 activation (24, 26), which enforce the senescence growth arrest (Figure 2).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [24]
Telomere-binding proteins inhibit DNA repair in cis to maintain linear chromosome structure and prevent fusions.
“These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair in cis18,19 to maintain the linear structure of chromosomes and to prevent fusions.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [19]
DNA damage within telomeric repeats resists repair, causing persistent tDDR signalling and TAF formation even at long telomeres.
“As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres19–21.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [19]
Damaged telomeres increase in the brain, liver and skin of aged baboons.
“Damaged telomeres also increase in the brain, liver and skin of aged baboons19,38.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [19]
TAFs increase with age in hippocampal neurons of baboons and mice.
“TAFs increase with age in hippocampal neurons in baboons19 and mice151”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [19]
In vitro studies indicate telomerase expression cannot prevent accumulation of persistent double-strand breaks at telomeres after exogenous genotoxic insults.
“in vitro studies indicate that telomerase expression is not able to prevent the accumulation of persistent double-strand breaks at telomeres after exogenous genotoxic insults19,20”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [19]
Persistent DNA damage response activation also occurs at telomeres that are not critically shortened in non-dividing cells exposed to genotoxic treatments and in non-dividing ageing cells, because repair is less efficient at telomeric double-strand breaks.
“Persistent DDR activation occurs also at telomeres that are not critically shortened, in non-dividing cells exposed to exogenous genotoxic treatments and in non-dividing ageing cells, because repair is much less efficient when DSBs are localized within telomeres35–37”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [35]
During ageing, terminally differentiated cells can accumulate persistent DNA damage and DDR markers.
“during ageing terminally differentiated cells can accumulate persistent DNA damage and DDR markers35,89”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [35]
Stress exposure leads to activation of a persistent DDR at telomeric regions.
“Work by us and others previously demonstrated demonstrated that stress exposure leads to activation of a persistent DDR at telomeric regions”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Fumagalli et al, 2012
TRF2-dependent suppression of DNA repair within telomeres can yield DDR signaling from telomere-associated damage resulting from causes other than telomere shortening.
“In addition, the TRF2-dependent suppression of DNA repair within telomeres can yield DDR signaling from telomere-associated damage resulting from causes other than telomere shortening (Karlseder et al. 2002; Fumagalli et al. 2012).”
From Cellular senescence and its effector programs (2014) · cites this paper as Fumagalli et al. 2012
TRF2 protects chromosomal ends but also limits DNA repair when damage occurs within telomeres.
“It has been shown that the shelterin protein TRF2 protects chromosomal ends (van Steensel et al. 1998) but also limits DNA repair when damage occurs within telomeres (Fumagalli et al. 2012).”
From Cellular senescence and its effector programs (2014) · cites this paper as Fumagalli et al. 2012
If DNA damage is dispersed throughout the genome, damage within telomeres is irreparable and stabilized.
“If DNA damage is dispersed throughout the genome (e.g., by γ-irradiation), damage within telomeres is irreparable and thus stabilized (Fumagalli et al. 2012; Hewitt et al. 2012; Suram et al. 2012).”
From Cellular senescence and its effector programs (2014) · cites this paper as Fumagalli et al. 2012
SA-β-gal reflects the activity of a lysosomal enzyme that cleaves terminal β-D-galactose residues from β-D-galactosides.
“One of the most recognizable and common markers of cellular senescence is senescence-associated beta-galactosidase (SA-β-gal)37, which reflects the activity of a lysosomal enzyme that cleaves terminal β-d-galactose residues from β-D-galactosides38.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [37]
The Results section reports high SA-β-gal activity as evidence of senescence, but does not explain the enzyme’s location or what it cleaves. Searches for lysosomal β-galactosidase and terminal galactose cleavage found no passage addressing the biochemical claim attached to this citation; page numbers were not available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredDifferent intrinsic (telomere attrition, hyperproliferation, oxidative damage) and extrinsic (γ-irradiation, ultraviolet radiations, chemotherapeutic drugs) stimuli lead to persistent DDR signaling, which results in irreparable DNA damage and induces cellular senescence.
“Different intrinsic (telomere attrition, hyperproliferation, oxidative damage) and extrinsic (γ-irradiation, ultraviolet radiations, chemotherapeutic drugs) stimuli lead to persistent DDR signaling which results in irreparable DNA damage and induce cellular senescence (D’Adda Di Fagagna, 2008; Fumagalli et al., 2012).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Fumagalli et al., 2012
Prolonged DDR signaling caused directly or indirectly by DNA DSBs can enforce senescence growth arrest mostly regulated via the p53/p21WAF1/CIP1 pathway.
“Prolonged DDR signaling caused directly or indirectly by DNA DSBs can enforce senescence growth arrest mostly regulated via the p53/p21WAF1/CIP1 pathway (Fumagalli et al., 2012).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Fumagalli et al., 2012
An unprotected telomere resembles a persistent DNA double-strand break and triggers chronic DNA damage response activation, resulting in replicative senescence.
“An unprotected telomere resembles a persistent DNA double strand break (DSB) triggering chronic DDR activation resulting in replicative senescence12.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [12]
Expressing TRF2 adjacent to a DSB in mammalian cells leads to persistent DNA damage.
“expressing TRF2 adjacent to a DSB in mammalian cells leads to persistent DNA damage, providing further evidence to the irreparability of telomeres (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Recruitment of ligase IV in response to DNA damage is impaired when DSBs are generated adjacent to telomeric repeats in budding yeast.
“recruitment of ligase IV as a response to DNA damage is impaired when double-stranded breaks (DSBs) are generated adjacent to telomeric repeats in budding yeast (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
TRF2 is often still present at damaged telomeres when cells are exposed to stress, suggesting that loss of shelterin components is not the sole cause of telomere dysfunction.
“others have recently shown that TRF2 was often still present at damaged telomeres when cells were exposed to stress, suggesting that loss of shelterin components is not the sole cause of telomere dysfunction (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Persistent telomeric DDR signaling in response to genotoxic stress occurs irrespectively of length in human fibroblasts in vitro and mouse neurons in vivo.
“persistent telomeric DDR signaling in response to genotoxic stress has been shown to occur irrespectively of length in human fibroblasts in vitro and in mouse neurons in vivo (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Length-independent telomere damage is observed in hippocampal neurons and liver of baboons with age.
“Length-independent telomere damage has also been observed in hippocampal neurons and liver of baboons with age”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
DNA damage is more likely to occur at long telomeres because they represent a more abundant target for lesion formation.
“It has been suggested that DNA damage is more likely to occur at long telomeres as they represent a more abundant target for lesion formation, possibly explaining the occurrence of length-independent DDR activation (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Telomeric lesions remain unrepaired for several months both in vitro and in vivo.
“studies have shown that telomeric lesions remain unrepaired for several months both in vitro and in vivo (Fumagalli et al., 2012, Hewitt et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Telomeres signaling a persistent DDR are observed in hippocampal neurons of mice even three months after exposure to genotoxic stress.
“telomeres signaling a persistent DDR were observed in hippocampal neurons of mice even three months after they were exposed to genotoxic stress (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Persistent telomeric DNA damage is a feature of replicative, stress- and oncogene-induced senescence.
“persistent telomeric DNA damage is a feature of replicative, stress- and oncogene-induced senescence”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Unrepaired telomeres provide a source of persistent DDR signaling important to the establishment of senescence.
“it has been suggested that unrepaired telomeres provide a source of persistent DDR signaling which is important to the establishment of senescence (Fumagalli et al., 2012).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Fumagalli et al., 2012
Activation of the DNA damage checkpoint induces cellular senescence, an irreversible cell cycle arrest triggered by stresses including telomere shortening.
“an important downstream consequence of activation of the DNA damage checkpoint is induction of cellular senescence—an irreversible cell cycle arrest induced in response to cellular stresses, including telomere shortening57–59.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [57]
Telomeric lesions occur irrespective of telomere length and the presence or absence of the enzyme telomerase.
“Interestingly, these telomeric lesions occur irrespectively of telomere length and the presence or absence of the enzyme telomerase (Fumagalli et al., 2012;Hewitt et al., 2012).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Fumagalli et al., 2012
Telomere damage irrespective of length has also been observed with age in hippocampal neurons and in the liver of baboons.
“Telomere damage irrespectively of length has also been observed with age in hippocampal neurons and in the liver of baboons (Fumagalli et al., 2012).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Fumagalli et al., 2012
TRF2 binds all along the telomeric array and inhibits DSB repair completion by blocking the recruitment of ligase IV to DNA breaks that are located in or next to telomeric DNA.
“TRF2 binds all along the telomeric array [116] and inhibits DSB repair completion by blocking the recruitment of ligase IV to DNA breaks that are located in or next to telomeric DNA [109,115].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [115]
The accumulation of persistent and unresolved telomeric damage might be explained by the cell inability to efficiently repair damaged telomeres.
“The accumulation of persistent and unresolved telomeric damage might be explained by the cell inability to efficiently repair damaged telomeres [109,115].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [115]
Lesions in or next to telomeres are refractory to repair as a result of TRF2 presence.
“In fact, lesions in or next to telomeres are refractory to repair as a result of TRF2 presence.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [115]
When cells are exposed to oxidative or DNA damaging agents, if the damage occurs in telomeric regions, TRF2 inhibits its repair and contributes to an unresolved DDR, which helps to stabilize the senescence arrest.
“Similarly, when cells are exposed to oxidative or DNA damaging agents, if the damage occurs in telomeric regions, TRF2 inhibits its repair and contributes to an unresolved DDR, which helps to stabilize the senescence arrest [115].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [115]
Telomeres of various non-proliferative tissues, including the brain, are particularly resistant to DNA repair and can undergo persistent DNA damage response even without being critically short.
“Still, it has been shown that telomeres of various non-proliferative tissues, including the brain, are particularly resistant to DNA repair and can undergo persistent DNA damage response (DDR) even without being critically short [35].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [35]
Post-mitotic cells can assume a senescence-like phenotype.
“it reasons that post-mitotic cells, too, can assume a senescence-like phenotype”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Fumagalli et al., 2012
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Telomere dysfunction in ageing and age-related diseases
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Self-citationRole of Telomeres and Telomerase in Aging and Cancer
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Length-independent telomere damage drives post-mitotic cardiomyocyte senescence
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“We and others have reported that stress-induced telomere damage can also lead to telomere dysfunction and induce senescence (Fumagalli et al , 2012; Hewitt et al , 2012).”
Mechanisms underlying T cell ageing
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Autophagic cell death restricts chromosomal instability during replicative crisis
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“Studies on aged mouse hepatocytes have shown the presence of senescence-associated markers such as SA-β-gal activity 157 , TAF 54,158 , karyomegaly and SADS 159 , LINE-1 expression 23 and expression of SASP factors 141 .”
Guidelines for minimal information on cellular senescence experimentation in vivo
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Cellular senescence: all roads lead to mitochondria
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Stress, cell senescence and organismal ageing
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Cellular senescence in brain aging
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“In fact, data suggest that telomeres might be the source of persistent DDR, even without overt telomere shortening in various mouse tissues including brain (Fumagalli et al., 2012; Hewitt et al., 2012).”
BackgroundAging of the cells: Insight into cellular senescence and detection Methods.
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“Shortened telomeres induce a DDR that leads to a growth arrest, during which cells attempt to repair the damage and, if DNA damage is irreparable, triggers replicative senescence (Zou et al., 2004; Fumagalli et al., 2012).”
Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction
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NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma
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Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
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Telomerase Is Required for Zebrafish Lifespan
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Self-citationThe DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
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Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction
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From cellular senescence to Alzheimer’s disease: The role of telomere shortening
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Questioning causal involvement of telomeres in aging
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Self-citationTemporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk
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To clear, or not to clear (senescent cells)? That is the question
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Cellular senescence and tumor promotion: Is aging the key?
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Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics
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From “Cellular” RNA to “Smart” RNA: Multiple Roles of RNA in Genome Stability and Beyond
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Self-citationShort-term gain, long-term pain: the senescence life cycle and cancer
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Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
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Self-citationHomologous recombination-dependent repair of telomeric DSBs in proliferating human cells
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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts
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Self-citationAnti‐inflammatory treatment rescues memory deficits during aging in <i>nfkb1</i><sup>−/−</sup> mice
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Self-citationTherapeutic Potential of Senolytics in Cardiovascular Disease
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Senescence and the Pro-tumorigenic Stroma
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DNA damage response at telomeres boosts the transcription of SARS‐CoV‐2 receptor ACE2 during aging
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Ciliary abnormalities in senescent human fibroblasts impair proliferative capacity
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- Authors
- Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., Bucci, G., Dobreva, M., Matti, V., Beausejour, C. M., Herbig, U., Longhese, M. P., & d’Adda di Fagagna, F.
- Affiliations
- IFOM (IT)
- University of Milano-Bicocca (IT)
- European Institute of Oncology (IT)
- Italian Institute of Technology (IT)
- Rutgers New Jersey Medical School (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2012-03-18
- Volume
- 14
- Issue
- 4
- Pages
- 355-365
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3717580
- OpenAlex
- W2046466087
- Cited by
- 851
- References
- 55
- Citations by year
- 2026: 44 · 2025: 51 · 2024: 57 · 2023: 66 · 2022: 80 · 2021: 85 · 2020: 68 · 2019: 56 · 2018: 49 · 2017: 55 · 2016: 51 · 2015: 64 · 2014: 51 · 2013: 50 · 2012: 24
- FWCI
- 40.53
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-05-02)
- Open access
- green
- europepmc.org
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (IAO-79317)
- National Cancer Institute (R01CA136533)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomeric DNA, DNA damage response, cellular senescence, TRF2, DNA double-strand break repair, DNA damage foci, telomere length, aging
- MeSH terms
- Animals, Cell Cycle, Cells, Cultured, DNA Damage, Fibroblasts, HeLa Cells, Humans, Neurons, Telomere, Telomeric Repeat Binding Protein 2, Mice
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