The Telomere Deprotection Response Is Functionally Distinct from the Genomic DNA Damage Response
Open accessAbstract
Loss of chromosome end protection through telomere erosion is a hallmark of aging and senescence. Here we developed an experimental system that mimics physiological telomere deprotection in human cells and discovered that the telomere deprotection response is functionally distinct from the genomic DNA damage response. We found that, unlike genomic breaks, deprotected telomeres that are recognized as DNA damage but remain in the fusion-resistant intermediate state activate differential ataxia telangiectasia mutated (ATM) signaling where CHK2 is not phosphorylated. Also unlike genomic breaks, we found that deprotected telomeres do not contribute to the G2/M checkpoint and are instead passed through cell division to induce p53-dependent G1 arrest in the daughter cells. Telomere deprotection is therefore an epigenetic signal passed between cell generations to ensure that replication-associated telomere-dependent growth arrest occurs in stable diploid G1 phase cells before genome instability can occur.
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DNA damage signaling from partial telomere deprotection is insufficient to fully activate the ATM-mediated G2/M checkpoint; after mitosis, DNA damage induces p53-dependent G1 exit.
“In agreement with this hypothesis, a recent report showed that, unlike genomic breaks, DNA damage signaling elicited by partial telomere deprotection is insufficient to fully activate the ATM-mediated G2/M checkpoint.83 Instead, after completion of mitosis, DNA damage induces p53-dependent cell cycle exit in G1.”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [83]
Transient Chk1/2 activation from partial TRF2 depletion or acute DNA damage, when p21 induction is inefficient, can delay but not prevent mitosis.
“Conversely, transient Chk1/2 activation, induced by partial TRF2 depletion 83 or acute DNA damage (by IR), 93 in the absence of (efficient) p21 induction can transiently delay, but not prevent mitosis.”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [83]
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 [83]
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Cites
Mammalian Telomeres End in a Large Duplex Loop
Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., & de Lange, T. (1999) · Cell · doi:10.1016/s0092-8674(00)80760-6 · Cited by 2,447 · see citing works
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Deng, C., Zhang, P., Wade Harper, J., Elledge, S. J., & Leder, P. (1995) · Cell · doi:10.1016/0092-8674(95)90039-x · Cited by 2,113 · see citing works
Essential role of mouse telomerase in highly proliferative organs
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998) · Nature · doi:10.1038/33345 · Cited by 1,270 · cited 1× · see citing works
“This comes at the price of p53 activation by intermediatestate telomeres, contributing to tissue degradation in the telomere syndromes and during the aging program (Armanios and Blackburn, 2012; Lee et al., 1998).”
Backgroundp21 is necessary for the p53-mediated G1 arrest in human cancer cells.
Waldman, T. A., Kinzler, K. W., & Vogelstein, B. (1995) · PubMed · Cited by 1,203 · see citing works
Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice
Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000) · Nature · doi:10.1038/35020592 · Cited by 1,085 · see citing works
Armanios, M., & Blackburn, E. H. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3246 · Cited by 982 · see citing works
Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · cited 1× · see citing works
“It has been known for some time that loss of p53 cooperates with telomere dysfunction to drive oncogenesis; however, the underlying mechanism was unclear (Chin et al., 1999).”
Escribano‐Diaz, C., Orthwein, A., Fradet‐Turcotte, A., Xing, M., Young, J. T. F., Tkáč, J., Cook, M. A., Rosebrock, A. P., Munro, M., Canny, M. D., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.001 · Cited by 903 · see citing works
Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1
Denchi, E. L., & de Lange, T. (2007) · Nature · doi:10.1038/nature06065 · Cited by 880 · see citing works
Senescence Induced by Altered Telomere State, Not Telomere Loss
Karlseder, J., Smogorzewska, A., & de Lange, T. (2002) · Science · doi:10.1126/science.1069523 · Cited by 796 · see citing works
Self-citationATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
Lim, D.-S., Kim, S.-T., Xu, B., Maser, R. S., Lin, J., Petrini, J. H. J., & Kastan, M. B. (2000) · Nature · doi:10.1038/35007091 · Cited by 786 · see citing works
Chapman, J. R., Barral, P., Vannier, J., Borel, V., Steger, M., Tomás‐Loba, A., Sartori, A. A., Adams, I. R., Batista, F. D., & Boulton, S. J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.002 · Cited by 624 · see citing works
DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion
Celli, G. B., & de Lange, T. (2005) · Nature Cell Biology · doi:10.1038/ncb1275 · Cited by 623 · see citing works
Regulation of DNA Damage Responses by Ubiquitin and SUMO
Jackson, S. P., & Durocher, D. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.017 · Cited by 601 · see citing works
53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility
Dimitrova, N., Chen, Y.-C. M., Spector, D. L., & de Lange, T. (2008) · Nature · doi:10.1038/nature07433 · Cited by 572 · see citing works
T‐loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang
Stansel, R. M., de Lange, T., & Griffith, J. D. (2001) · The EMBO Journal · doi:10.1093/emboj/20.19.5532 · Cited by 529 · see citing works
Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres
O'Sullivan, R. J., Kubicek, S., Schreiber, S. L., & Karlseder, J. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1897 · Cited by 416 · see citing works
Self-citationKarlseder, J., Hoke, K., Mirzoeva, O. K., Bakkenist, C. J., Kastan, M. B., Petrini, J. H. J., & de Lange, T. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020240 · Cited by 393 · see citing works
Self-citationCelli, G. B., Denchi, E. L., & de Lange, T. (2006) · Nature Cell Biology · doi:10.1038/ncb1444 · Cited by 320 · see citing works
Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions
Cesare, A. J., Kaul, Z., Cohen, S. B., Napier, C. E., Pickett, H. A., Neumann, A. A., & Reddel, R. R. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1725 · Cited by 263 · see citing works
Self-citationChromosome breakage after G2 checkpoint release
Deckbar, D., Birraux, J., Krempler, A., Tchouandong, L., Beucher, A., Walker, S., Stiff, T., Jeggo, P., & Löbrich, M. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200612047 · Cited by 252 · see citing works
A two-step mechanism for TRF2-mediated chromosome-end protection
Okamoto, K., Bartocci, C., Ouzounov, I., Diedrich, J. K., Yates, J. R., & Denchi, E. L. (2013) · Nature · doi:10.1038/nature11873 · Cited by 240 · see citing works
Five dysfunctional telomeres predict onset of senescence in human cells
Kaul, Z., Cesare, A. J., Huschtscha, L. I., Neumann, A. A., & Reddel, R. R. (2012) · The EMBO Reports · doi:10.1038/embor.2011.227 · Cited by 225 · cited 10× · see citing works
“These results are consistent with previous observations of spontaneous telomere deprotection in aged cells (Kaul et al., 2012) and indicate that these deprotected mitotic telomeres were inherited from the previous G2 phase.”
BackgroundMethodResultInfluentialSelf-citationA telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
Hayashi, M., Cesare, A. J., Fitzpatrick, J. A. J., Denchi, E. L., & Karlseder, J. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2245 · Cited by 166 · see citing works
Self-citationHow Shelterin Solves the Telomere End-Protection ProblemPreprint
de Lange, T. (2010) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2010.75.017 · Cited by 157 · see citing works
Human Telomeres Are Tethered to the Nuclear Envelope during Postmitotic Nuclear Assembly
Crabbé, L., Cesare, A. J., Kasuboski, J. M., Fitzpatrick, J. A. J., & Karlseder, J. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.019 · Cited by 147 · see citing works
Self-citationChfr and RNF8 synergistically regulate ATM activation
Wu, J., Chen, Y., Lu, L., Wu, Y., Paulsen, M. T., Ljungman, M. E., Ferguson, D. O., & Yu, X. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2078 · Cited by 107 · see citing works
A three-state model of telomere control over human proliferative boundaries
Cesare, A. J., & Karlseder, J. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.08.007 · Cited by 106 · see citing works
Self-citationGong, Y., & de Lange, T. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.016 · Cited by 102 · see citing works
Pampalona, J., Frías-López, C., Genescà, A., & Tusell, L. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002679 · Cited by 96 · see citing works
ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres
Thanasoula, M., Escandell, J. M., Suwaki, N., & Tarsounas, M. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.191 · Cited by 93 · see citing works
Telomeres avoid end detection by severing the checkpoint signal transduction pathway
Carneiro, T., Khair, L., Reis, C. C., Borges, V., Moser, B. A., Nakamura, T. M., & Ferreira, M. G. (2010) · Nature · doi:10.1038/nature09353 · Cited by 75 · see citing works
DNA-damage response and repair activities at uncapped telomeres depend on RNF8
Peuscher, M. H., & Jacobs, J. J. L. (2011) · Nature Cell Biology · doi:10.1038/ncb2326 · Cited by 69 · see citing works
The Shelterin Protein TRF2 Inhibits Chk2 Activity at Telomeres in the Absence of DNA Damage
Buscemi, G., Zannini, L., Fontanella, E., Lecis, D., Lisanti, S., & Delia, D. (2009) · Current Biology · doi:10.1016/j.cub.2009.03.064 · Cited by 47 · see citing works
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Blackburn, E. H., Epel, E. S., & Lin, J. (2015) · Science · doi:10.1126/science.aab3389 · Cited by 1,596 · see citing works
Shelterin-Mediated Telomere Protection
de Lange, T. (2018) · Annual Review of Genetics · doi:10.1146/annurev-genet-032918-021921 · Cited by 816 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
Senescence from G2 arrest, revisited
Gire, V., & Dulić, V. (2015) · Cell Cycle · doi:10.1080/15384101.2014.1000134 · Cited by 300 · see citing works
Telomere-driven diseases and telomere-targeting therapies
Martínez, P., & Blasco, M. A. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201610111 · Cited by 257 · see citing works
“…point, named the intermediate telomere state, telomeres are too short to be fully functional and are presumably unable to form the T-loop structure but retain sufficient protective shelterin to inhibit end-to-end fusions (Cesare et al., 2009, 2013; Kaul et al., 2011; Cesare and Karlseder, 2012).”
BackgroundCellular senescence in the aging and diseased kidney
Valentijn, F. A., Falke, L. L., Nguyen, T. Q., & Goldschmeding, R. (2018) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-017-0434-2 · Cited by 173 · see citing works
Cell death during crisis is mediated by mitotic telomere deprotection
Hayashi, M. T., Cesare, A. J., Rivera, T., & Karlseder, J. (2015) · Nature · doi:10.1038/nature14513 · Cited by 125 · see citing works
Self-citationLudlow, A. T., Ludlow, L. W., & Roth, S. M. (2013) · BioMed Research International · doi:10.1155/2013/601368 · Cited by 93 · see citing works
The end protection problem—an unexpected twist in the tail
Ruis, P., & Boulton, S. J. (2021) · Genes & Development · doi:10.1101/gad.344044.120 · Cited by 57 · see citing works
Tanaka, H., Beam, M. J., & Caruana, K. (2014) · Neoplasia · doi:10.1016/j.neo.2014.08.009 · Cited by 19 · see citing works
- Authors
- Cesare, A. J., Hayashi, M. T., Crabbe, L., & Karlseder, J.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Karlseder, Jan
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 51
- Issue
- 2
- Pages
- 141-155
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3721072
- OpenAlex
- W2033673317
- Cited by
- 155
- References
- 34
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 11 · 2022: 7 · 2021: 16 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 10 · 2015: 17 · 2014: 22 · 2013: 6
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- University of California, Irvine
- National Cancer Institute (T32CA009370, P30CA014195)
- National Institute of General Medical Sciences (GM087476, R01GM087476)
- 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
- telomere shortening, DNA damage response, ATM signaling, Chk2 phosphorylation, G1 cell cycle arrest, p53, G2/M checkpoint, genomic instability, cellular senescence, aging, telomere fusion
- MeSH terms
- Cell Division, DNA Damage, DNA Replication, Flow Cytometry, Fluorescent Antibody Technique, Humans, Mitosis, Blotting, Western, Transcriptional Activation, Genome, Human, Tumor Suppressor Protein p53, G2 Phase, Telomere, Cellular Senescence, Telomeric Repeat Binding Protein 2, Immunoprecipitation, Cell Proliferation, Cell Cycle Checkpoints
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