Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions
Abstract
Telomere dysfunction is typically studied under conditions in which a component of the six-subunit shelterin complex that protects chromosome ends is disrupted. The nature of spontaneous telomere dysfunction is less well understood. Here we report that immortalized human cell lines lacking wild-type p53 function spontaneously show many telomeres with a DNA damage response (DDR), commonly affecting only one sister chromatid and not associated with increased chromosome end-joining. DDR(+) telomeres represent an intermediate configuration between the fully capped and uncapped (fusogenic) states. In telomerase activity-positive (TA(+)) cells, DDR is associated with low TA and short telomeres. In cells using the alternative lengthening of telomeres mechanism (ALT(+)), DDR is partly independent of telomere length, mostly affects leading strand-replicated telomeres, and can be partly suppressed by TRF2 overexpression. In ALT(+) (but not TA(+)) cells, DDR(+) telomeres preferentially associate with large foci of extrachromosomal telomeric DNA and recombination proteins. DDR(+) telomeres therefore arise through different mechanisms in TA(+) and ALT(+) cells and have different consequences.
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Telomeres may exist in three different states: fully capped or closed, intermediate, and fully uncapped.
“Roger Reddel's group have suggested that telomeres may exist in three different states, providing an explanation to DNA damage signaling at telomeres that still contain shelterin proteins.”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Cesare et al., 2009
In the fully capped state, telomeric repeats are sufficiently long that T-loop conformation is not compromised, and shelterin proteins inhibit NHEJ, preventing DDR activation.
“The first state is the so-called fully capped or closed state, where telomeric repeats are sufficiently long such that the T-loop conformation is not compromised, and shelterin proteins inhibit NHEJ, preventing DDR activation.”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Cesare et al., 2009
Extreme telomere shortening can disrupt the T-loop, causing DDR activation (fully uncapped), loss of shelterin proteins, and end-to-end fusions.
“extreme telomere shortening can lead to disruption of the T-loop, causing DDR activation, a state also known as fully uncapped. In the latter, telomeric repeats have reached critical lengths such that there is a loss of shelterin proteins and NHEJ is no longer inhibited at telomeres, causing end-to-end fusions (Cesare et al., 2009).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Cesare et al., 2009
If T-loop conformation is lost, telomeres may adopt an intermediate state, activating a DDR without end-to-end fusions due to sufficient shelterin proteins.
“if T-loop conformation is lost, telomeres may adopt an intermediate state, activating a DDR without leading to end-to-end fusions due to the presence of sufficient shelterin proteins.”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Cesare et al., 2009
Cites
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · see citing works
p53- and ATM-Dependent Apoptosis Induced by Telomeres Lacking TRF2
Karlseder, J., Broccoli, D., Dai, Y., Hardy, S., & de Lange, T. (1999) · Science · doi:10.1126/science.283.5406.1321 · Cited by 1,086 · see citing works
Different telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482 · cited 1× · see citing works
“The p53-mediated cellular arrest that occurs in response to telomere dysfunction is thought to involve a DDR checkpoin”
BackgroundReplication and protection of telomeres
Verdun, R. E., & Karlseder, J. (2007) · Nature · doi:10.1038/nature05976 · Cited by 463 · see citing works
Wu, L., Multani, A. S., He, H., Cosme-Blanco, W., Deng, Y., Deng, J. M., Bachilo, O., Pathak, S., Tahara, H., Bailey, S. M., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.037 · Cited by 422 · see citing works
Celli, G. B., Denchi, E. L., & de Lange, T. (2006) · Nature Cell Biology · doi:10.1038/ncb1444 · Cited by 320 · see citing works
Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis
Guo, X., Deng, Y., Lin, Y., Cosme‐Blanco, W., Chan, S., He, H., Yuan, G., Brown, E. J., & Chang, S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601893 · Cited by 258 · see citing works
A RAP1/TRF2 Complex Inhibits Nonhomologous End-Joining at Human Telomeric DNA Ends
Bae, N. S., & Baumann, P. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.023 · Cited by 215 · see citing works
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Hewitt, G., Jurk, D., Marques, F. D. M., Correia-Melo, C., Hardy, T., Gackowska, A., Anderson, R., Taschuk, M., Mann, J., & Passos, J. F. (2012) · Nature Communications · doi:10.1038/ncomms1708 · Cited by 908 · see citing works
Lovejoy, C. A., Li, W., Reisenweber, S., Thongthip, S., Bruno, J., de Lange, T., De, S., Petrini, J. H. J., Sung, P. A., Jasin, M., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002772 · Cited by 629 · see citing works
“These spontaneous 53BP1 foci could be the result of both genome-wide DNA breaks and the presence of dysfunctional telomeres [52].”
BackgroundSelf-citationAutophagic cell death restricts chromosomal instability during replicative crisis
Nassour, J., Radford, R., Correia, A., Fusté, J. M., Schoell, B., Jauch, A., Shaw, R. J., & Karlseder, J. (2019) · Nature · doi:10.1038/s41586-019-0885-0 · Cited by 429 · see citing works
Telomeres and cell senescence—size matters not
Victorelli, S., & Passos, J. F. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.027 · Cited by 413 · 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
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).”
BackgroundFive 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 · see citing works
“We expect segregation of chromatid-or chromosome-type meta-TIFs to result in one or both daughter cells, respectively, inheriting a TIF (supplementary”
InfluentialSelf-citationMolecular mechanisms of activity and derepression of alternative lengthening of telomeres
Pickett, H. A., & Reddel, R. R. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3106 · Cited by 203 · see citing works
Self-citationGao, X., Yu, X., Zhang, C., Wang, Y., Sun, Y., Sun, H., Zhang, H., Shi, Y., & He, X. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10370-8 · Cited by 180 · see citing works
The Telomere Deprotection Response Is Functionally Distinct from the Genomic DNA Damage Response
Cesare, A. J., Hayashi, M. T., Crabbe, L., & Karlseder, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.006 · Cited by 155 · see citing works
Self-citationNuRD–ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination
Conomos, D., Reddel, R. R., & Pickett, H. A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2877 · Cited by 129 · see citing works
Self-citationCell 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-citationMorgan, R. G., Ives, S. J., Lesniewski, L. A., Cawthon, R. M., Andtbacka, R. H. I., Noyes, R. D., Richardson, R. S., & Donato, A. J. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00197.2013 · Cited by 115 · 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-citationOsterwald, S., Deeg, K. I., Chung, I., Parisotto, D., Wörz, S., Rohr, K., Erfle, H., & Rippe, K. (2015) · Journal of Cell Science · doi:10.1242/jcs.148296 · Cited by 92 · see citing works
Beauvarlet, J., Bensadoun, P., Darbo, E., Labrunie, G., Rousseau, B., Richard, E., Draskovic, I., Londono-Vallejo, A., Dupuy, J.-W., Nath Das, R., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz095 · Cited by 73 · see citing works
Ahmad, T., Sundar, I. K., Tormos, A. M., Lerner, C. A., Gerloff, J., Yao, H., & Rahman, I. (2017) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0198oc · Cited by 67 · 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
Zhang, X., Li, B., de Jonge, N., Björkholm, M., & Xu, D. (2015) · Oncotarget · doi:10.18632/oncotarget.2917 · Cited by 38 · see citing works
- Authors
- Cesare, A. J., Kaul, Z., Cohen, S. B., Napier, C. E., Pickett, H. A., Neumann, A. A., & Reddel, R. R.
- Affiliations
- Children's Medical Research Institute (AU)
- The University of Sydney (AU)
- Corresponding author
- Reddel, Roger R
- Venue
- Nature Structural & Molecular Biology
- Published
- 2009-11-22
- Volume
- 16
- Issue
- 12
- Pages
- 1244-1251
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W1966346464
- Cited by
- 263
- References
- 8
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 13 · 2023: 25 · 2022: 13 · 2021: 19 · 2020: 19 · 2019: 22 · 2018: 13 · 2017: 20 · 2016: 15 · 2015: 15 · 2014: 15 · 2013: 15 · 2012: 16
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- shelterin complex, TRF2, telomere dysfunction, telomerase, alternative lengthening of telomeres, chromosome fusion, p53 deficiency, telomere length, sister chromatids, telomere capping
- MeSH terms
- Cell Line, Chromosomes, Human, DNA Damage, Humans, Models, Biological, Telomere, Telomerase, Telomeric Repeat Binding Protein 2, Recombinases
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