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Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-loop Formation
Open accessAbstract
We have applied a super-resolution fluorescence imaging method, stochastic optical reconstruction microscopy (STORM), to visualize the structure of functional telomeres and telomeres rendered dysfunctional through removal of shelterin proteins. The STORM images showed that functional telomeres frequently exhibit a t-loop configuration. Conditional deletion of individual components of shelterin showed that TRF2 was required for the formation and/or maintenance of t-loops, whereas deletion of TRF1, Rap1, or the POT1 proteins (POT1a and POT1b) had no effect on the frequency of t-loop occurrence. Within the shelterin complex, TRF2 uniquely serves to protect telomeres from two pathways that are initiated on free DNA ends: classical nonhomologous end-joining (NHEJ) and ATM-dependent DNA damage signaling. The TRF2-dependent remodeling of telomeres into t-loop structures, which sequester the ends of chromosomes, can explain why NHEJ and the ATM signaling pathway are repressed when TRF2 is present.
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“Telomeres are repetitive DNA sequences, bound by the six-subunit shelterin complex [86] that facilitates the formation of telomere loops (t-loop) to hide the telomere end [87,88], thus protecting the natural chromosome ends from signaling pathways that sense and act at DNA breaks.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [88]
In the citing paper
“In agreement, TRF2 overexpression delays replicative senescence onset [101], indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation [88] might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [88]
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Citations
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Photoswitchable Fluorescent Hydrazone for Super-Resolution Cell Membrane Imaging
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Hou, K., Yu, Y., Li, D., Zhang, Y., Zhang, K., Tong, J., Yang, K., & Jia, S. (2022) · Cancers · doi:10.3390/cancers14092194 · Cited by 25
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Bifunctional Super-resolution Imaging Probe with Acidity-Independent Lysosome-Retention Mechanism
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“Telomeres are terminated by a single-stranded 3 ′ overhang that can strand-invade into the upstream double-stranded telomeric DNA to form a telomere loop (t-loop) ( Doksani et al., 2013 ; Griffith et al., 1999 ; Wang et al., 2004 ).”
Kaur, P., Barnes, R. P., Pan, H., Detwiler, A. C., Liu, M., Mahn, C., Hall, J. R., Messenger, Z. J., You, C., Piehler, J., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1142 · Cited by 21
“Results from both in vitro and cell-based experiments support the notion that TRF2 is the crucial player in T-loop formation, in which the 3 overhang invades the double-stranded telomeric DNA region (13,15,16).”
InfluentialYing, Y., Hu, X., Peng, H., Méndez-Bermúdez, A., Bauwens, S., Eid, R., Tan, L., Pousse, M., Giraud-Panis, M.-J. E., Lu, Y., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac065 · Cited by 21
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Horrocks, M. H., Palayret, M., Klenerman, D., & Lee, S. F. (2014) · Histochemistry and Cell Biology · doi:10.1007/s00418-014-1186-1 · Cited by 20
TRF2 recruits ORC through TRFH domain dimerization
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TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang
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Probing transient protein-mediated DNA linkages using nanoconfinement
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TElomeric repeat-containing RNA (TERRA): Physiological functions and relevance in cancer
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“These structures are indispensable for the proper function of telomeres, and their formation has to be strictly regulated during the cell cycle by proteins of the shelterin multimeric complex (6, 7).”
BackgroundDNA-PK controls Apollo’s access to leading-end telomeres
Sönmez, C., Toia, B., Eickhoff, P., Matei, A. M., Beyrouthy, M. E., Wallner, B., Douglas, M. E., de Lange, T., & Lottersberger, F. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae105 · Cited by 20
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Super-resolution Microscopy for Biological Imaging
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Shedding light into the relevance of telomeres in human reproduction and male factor infertility†
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Extrachromosomal telomere DNA derived from excessive strand displacements
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Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction
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“The protein complex shelterin, consisting of TRF1, TRF2, TIN2, POT1, TPP1 and RAP1, binds to telomeric repeats and mediates the formation of a telomeric loop (T-loop) in which the single-stranded 3′-overhang is concealed in a D-loop (Griffith et al., 1999; Doksani et al., 2013).”
BackgroundInfluentialUnderstanding DNA organization, damage, and repair with super-resolution fluorescence microscopy
Miriklis, E. L., Rozario, A. M., Rothenberg, E., Bell, T. D. M., & Whelan, D. R. (2021) · Methods and Applications in Fluorescence · doi:10.1088/2050-6120/abf239 · Cited by 21
ZNF524 directly interacts with telomeric DNA and supports telomere integrity
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“In particular, the shelterin member TRF2 plays a central role in telomere protection: TRF2 is essential for both the formation and preservation of the t-loop, a structure that protects the open chromosome ends by strand invasion of the 3 ’ -overhang into the double-stranded telomeric region 3,7,8 .”
Telomere maintenance and the DNA damage response: a paradoxical alliance
Harman, A., & Bryan, T. M. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1472906 · Cited by 19
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“It has been hypothesized that telomere loops (t-loops) [51, 52] are the protective structure sequestering the distal chromosome end from DDR activation.”
BackgroundHigh‐throughput single‐molecule studies of protein–DNA interactions
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“The development of single-molecule experiments in cell-free extracts [10–12] and within living cells [13,14] will continue to shed critical insights into all aspects of genome maintenance.”
Adam, N., Degelman, E., Briggs, S., Wazen, R. M., Colarusso, P., Riabowol, K. T., & Beattie, T. L. (2019) · Communications Biology · doi:10.1038/s42003-019-0692-z · Cited by 16
Nuclear Accumulation of LAP1:TRF2 Complex during DNA Damage Response Uncovers a Novel Role for LAP1
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“telomeric DNA and facilitates its folding into a t-loop configuration that sequesters the terminal single strand of chromosome ends within the duplex region, thus preventing their misrecognition as DSBs by the DNA damage surveillance system [33,34].”
BackgroundPCNA, a focus on replication stress and the alternative lengthening of telomeres pathway
Shen, M. C., Young, A., & Autexier, C. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103055 · Cited by 21
Stem cells at odds with telomere maintenance and protection
Penev, A., Markiewicz-Potoczny, M., Sfeir, A., & Denchi, E. L. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.12.007 · Cited by 18
How homologous recombination maintains telomere integrity
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“These barriers to telomere replication are thought to be dismantled in vivo by PIF1, WRN, BLM or RTEL1 helicases, known to unwind G-quadruplexes in vitro (Ding et al. 2004; Fry and Loeb 1999; Huber et al. 2006; Opresko et al. 2003; Ribeyre et al. 2009; Sun et al. 1998).”
BackgroundHolliday Junctions Formed from Human Telomeric DNA
Haider, S. M., Li, P., Khiali, S., Munnur, D., Ramanathan, A., & Parkinson, G. N. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b08699 · Cited by 17
Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer
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Close Ties between the Nuclear Envelope and Mammalian Telomeres: Give Me Shelter
Pennarun, G., Picotto, J., & Bertrand, P. (2023) · Genes · doi:10.3390/genes14040775 · Cited by 17
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Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss
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“TRF2 is responsible for forming T-loop structure that sequester the ends of a chromosome, thereby preventing its recognition as a DSB and the activation of ATM (Sfeir and de Lange, 2012; Doksani et al., 2013).”
Telomere Repeat-Binding Factor 2 Is Responsible for the Telomere Attachment to the Nuclear Membrane
Ilicheva, N. V., Podgornaya, O. I., & Voronin, A. P. (2015) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2015.06.009 · Cited by 16
“For instance, TRF1 can loop, bend, and base-pair telomeric repeat arrays in vitro (de Lange, 2005), but deletion of this component has no effect on the t-loop frequency occurrence in vivo (Doksani et al., 2013).”
BackgroundChen, W., Wang, Y., Li, F., Lin, W., Liang, Y., & Ma, Z. (2017) · BioMed Research International · doi:10.1155/2017/9764752 · Cited by 16
The intrinsic ability of double-stranded DNA to carry out D-loop and R-loop formation
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“In vivo, TRF2 is required for telomere-loop formation, but TRF1 is not [57].”
BackgroundThe long and the short of TRF2 in neurogenesis
Grammatikakis, I., Zhang, P., Mattson, M. P., & Gorospe, M. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1222339 · Cited by 15
“DNA and elicits genotoxic response which can trigger apoptosis.(21,22) To prevent such genotoxic response, TRF2 protects”
BackgroundMehra, D., Adhikari, S., Banerjee, C., & Puchner, E. M. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac314 · Cited by 15
Rai, R., Biju, K., Sun, W., Sodeinde, T., Al-Hiyasat, A., Morgan, J. E., Ye, X., Li, X., Chen, Y., & Chang, S. S. (2023) · Nature Communications · doi:10.1038/s41467-023-37761-w · Cited by 14
“The N-terminalbasic domain(TRF2 B ) facilitates the formation ofa branchedDNA structuretoblockthe recruitment ofPARP1 andbranch migration by HJ resolvases to prevent the deleterious cleavage of T-loops 9,13 – 18 .”
InfluentialVisualizing biological reaction intermediates with DNA curtains
Zhao, Y., Jiang, Y., & Qi, Z. (2017) · Journal of Physics D Applied Physics · doi:10.1088/1361-6463/aa59cf · Cited by 16
Dynamics of TRF1 organizing a single human telomere
Li, X., Wang, M., Zheng, W., Huang, W., Wang, Z., Jin, K., Liu, L., & Yu, Z. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1222 · Cited by 15
“Super-resolution microscopy has been used in imaging telomere architecture and measuring telomere volume dynamics (6,30–32).”
Li, B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.699639 · Cited by 14
Hübner, B., von Otter, E., Ahsan, B., Wee, M. L., Henriksson, S., Ludwig, A., & Sandin, S. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac309 · Cited by 14
“Although it is unclear how such a t-loop forms, both this early and a subsequent super-resolution light microscopy study (28) showed that TRF2 plays an important role in generating or stabilizing the structure.”
Interstitial telomeric loops and implications of the interaction between TRF2 and lamin A/C
Smith, E. D., Garza-Gongora, A. G., MacQuarrie, K. L., & Kosak, S. T. (2018) · Differentiation · doi:10.1016/j.diff.2018.06.001 · Cited by 15
Sarlós, K., Biebricher, A. S., Peterman, E. J. G., Wuite, G. J. L., & Hickson, I. D. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.033647 · Cited by 14
“The telomeric DNA is looped back in a DNA structure called a T-loop that prevents the DNA end from being exposed (Griffith et al. 1999; Doksani et al. 2013).”
BackgroundAttenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen
Stuart, A., Takai, K., Gabbasova, R. R., Sanford, H., Vinogradova, E. V., & de Lange, T. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.11.006 · Cited by 13
Telomere length regulation in budding yeasts
Malyavko, A. N., Parfenova, Y. Y., Zvereva, M. I., & Донцова, О. А. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.05.049 · Cited by 14
“Mammalian telomeres were shown to form a fold-back structure (t-loop) by interaction of the 30-overhang with double-stranded telomeric DNA [27,28].”
BackgroundActin Dynamics Couples Extracellular Signals to the Mobility and Molecular Stability of Telomeres
Jokhun, D. S., Shang, Y., & Shivashankar, G. V. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.08.029 · Cited by 14
Communication between chromatin and homologous recombination
Verma, P., & Greenberg, R. A. (2021) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2021.05.006 · Cited by 15
Watson, J. M., Trieb, J., Troestl, M., Renfrew, K. B., Mandáková, T. M., Fulneček, J., Shippen, D. E., & Říha, K. (2021) · Genetics · doi:10.1093/genetics/iyab126 · Cited by 14
Storchova, R., Palek, M., Palková, N., Veverka, P., Brom, T., Hofr, C., & Macůrek, L. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1269 · Cited by 15
“Indeed, transient PPM1D inhibition increased activity of ATM as documented by increased le v el of KAP1-S824 phosphorylation (Figure 5 C).”
BackgroundMethodResultInfluentialE-type cyclins modulate telomere integrity in mammalian male meiosis
Manterola, M., Siciński, P., & Wolgemuth, D. J. (2015) · Chromosoma · doi:10.1007/s00412-015-0564-3 · Cited by 14
“…is correlated with reduced levels of TRF2 at the telomeres We have mentioned above that a proper balance of the proteins in the shelterin complex is essential for the maintenance of telomere integrity and function (Cesare et al. 2013; de Lange 2005; Doksani et al. 2013; Sfeir and de Lange 2012).”
Telomere uncapping at the crossroad between cell cycle arrest and carcinogenesis
Gobbini, E., Trovesi, C., Cassani, C., & Longhese, M. P. (2014) · Molecular & Cellular Oncology · doi:10.4161/mco.29901 · Cited by 15
Targeting Cellular Senescence: Pathophysiology in Multisystem Age-Related Diseases
Liu, J., Yu, H., & Xu, Y. (2025) · Biomedicines · doi:10.3390/biomedicines13071727 · Cited by 14
“The G-prominent end invades the double-stranded DNA to form a D-loop, which, in turn, further forms a higher-order chromatin structure termed the T-loop [10,11].”
Structural biology of shelterin and telomeric chromatin: the pieces and an unfinished puzzle
Hu, H., Yan, H. L., & Nguyen, T. H. D. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230300 · Cited by 12
Visualizing mechanical modulation of nanoscale organization of cell-matrix adhesions
Ou, G., Thakar, D., Tung, J. C., Miroshnikova, Y. A., DuFort, C. C., Gutierrez, E., Groisman, A., & Weaver, V. M. (2016) · Integrative Biology · doi:10.1039/c6ib00031b · Cited by 13
How stem cells keep telomeres in check
Li, J. S. Z., & Denchi, E. L. (2018) · Differentiation · doi:10.1016/j.diff.2018.01.004 · Cited by 17
“T-loop structures as well as binding of the shelterin complex ensure chromosome end protection from nucleolytic degradation and activation of the DNA damage response (Denchi, 2009; Denchi and de Lange, 2007; Doksani et al., 2013; Karlseder et al., 2004; Okamoto et al., 2013; Sfeir and de Lange, 2012).”
Purification of mammalian telomeric DNA for single-molecule analysis
Mazzucco, G., Huda, A., Galli, M. G., Zanella, E., & Doksani, Y. (2022) · Nature Protocols · doi:10.1038/s41596-022-00684-9 · Cited by 12
Self-citationLiang, F., Rai, R., Sodeinde, T., & Chang, S. S. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae642 · Cited by 12
“As the main telomere protector, TRF2 prevents the activation of ATM-dependent signaling and C-NHEJ-mediated telomere repair that would otherwise result in end-to-end chromosome fusions and cell death ( 8 , 9 , 11 ).”
TRF1 and TRF2 form distinct shelterin subcomplexes at telomeres
Janovič, T., Perez, G. I., Boelting, G., & Schmidt, J. C. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116178 · Cited by 13
Wand, T., Fang, M., Chen, C., Hardy, N., McCoy, J. P., Dumitriu, B., Young, N. S., & Biancotto, A. (2016) · Cytometry Part A · doi:10.1002/cyto.a.22982 · Cited by 12
“Consistent with their role in protecting telomere content, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts (23).”
BackgroundChanges in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors
Idilli, A. I., Pagani, F., Kerschbamer, E., Berardinelli, F., Bernabé‐García, M., Cayuela, M. L., Piazza, S., Poliani, P. L., Cusanelli, E., & Mione, M. (2020) · Cancers · doi:10.3390/cancers12041028 · Cited by 11
“Previous studies have indicated the shelterin complex as instrumental in preventing DNA replication stress and DNA damage response signaling through recruitment of helicase enzymes to telomeres [30–32] or formation of the T-loop structure [33,34].”
BackgroundCondensate-driven interfacial forces reposition DNA loci and measure chromatin viscoelasticityPreprint
Strom, A. R., Kim, Y., Zhao, H., Orlovsky, N. D., Chang, Y.-C., Košmrlj, A., Storm, C., & Brangwynne, C. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.27.530281 · Cited by 12
Soman, A., Korolev, N., & Nordenskiöld, L. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102492 · Cited by 12
The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin
Wong, S. Y., Soman, A., Korolev, N., Surya, W., Chen, Q., Shum, W. K., van Noort, J., & Nordenskiöld, L. (2023) · The EMBO Journal · doi:10.1038/s44318-023-00002-3 · Cited by 11
“TRF2 is a vital component of the shelterin complex for telomere protection by promoting the formation of the T-loop structure (Doksani et al, 2013; Grif fi th et al, 1999), repressing canonical non-homologous end-joining (Bae and Baumann, 2007; Doksani et al, 2013; Ribes-Zamora et al, 2013), and…”
Interaction of YOYO-3 with Different DNA Templates to Form H-Aggregates
Ruedas-Rama, M. J., Orte, Á., Martin-Domingo, M. C., Castello, F., Talavera, E. M., & Álvarez‐Pez, J. M. (2014) · The Journal of Physical Chemistry B · doi:10.1021/jp5022888 · Cited by 11
Developing bioimaging and quantitative methods to study 3D genome
Gao, J. T., Yang, X., Djekidel, M. N., Wang, Y., Xi, P., & Zhang, M. Q. (2016) · Quantitative Biology · doi:10.1007/s40484-016-0065-2 · Cited by 11
Dense small molecule labeling enables activator-dependent STORM by proximity mapping
Chen, Y., Gu, M., Gunning, P. W., & Russell, S. M. (2016) · Histochemistry and Cell Biology · doi:10.1007/s00418-016-1451-6 · Cited by 11
Greenwood, J., Patel, H., Cech, T. R., & Cooper, J. P. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky605 · Cited by 11
“Mammalian shelterin comprises the ds telomere-binding proteins TRF1 and TRF2, the ss telomere-binding proteins POT1 and TPP1, the TIN2 ss-ds bridging factor and the TRF2-interacting protein RAP1 (2,3).”
InfluentialEither Rap1 or Cdc13 can protect telomeric single-stranded 3′ overhangs from degradation in vitro
Runnberg, R., Narayanan, S., Itriago, H., & Cohn, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-55482-3 · Cited by 11
Role of Senescence and Neuroprotective Effects of Telomerase in Neurodegenerative Diseases
Ding, X., Liu, X., Wang, F., Wang, F., & Geng, X. (2019) · Rejuvenation Research · doi:10.1089/rej.2018.2115 · Cited by 12
“24 While the gradual shortening of terminal sequences occurs during DNA replication, there is evidence that telomeres undergo acute erosion in postmitotic neurons.”
Telomere Crisis Shapes Cancer EvolutionPreprint
Nassour, J., & Karlseder, J. (2025) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041688 · Cited by 16
Metadata
- Authors
- Doksani, Y., Wu, J. Y., de Lange, T., & Zhuang, X.
- Affiliations
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zhuang, Xiaowei
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 155
- Issue
- 2
- Pages
- 345-356
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4062873
- OpenAlex
- W2164580633
- Cited by
- 493
- References
- 69
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 46 · 2023: 36 · 2022: 31 · 2021: 51 · 2020: 40 · 2019: 37 · 2018: 47 · 2017: 42 · 2016: 45 · 2015: 45 · 2014: 36 · 2013: 4
- FWCI
- 30.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R56AG016642, AG016642, R01AG016642)
- National Institute of General Medical Sciences (R01GM068518, R37GM049046, R01GM049046, GM 068518, GM096450, R01GM096450, GM049046)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
- telomeres, T-loop, TRF2, shelterin, TRF1, Rap1, POT1, super-resolution fluorescence microscopy, storms, non-homologous end joining, ATM signaling, DNA damage response, telomere dysfunction, telomere protection
- MeSH terms
- Shelterin Complex, Animals, DNA-Binding Proteins, Fibroblasts, Microscopy, Fluorescence, Telomere, Telomere-Binding Proteins, Telomeric Repeat Binding Protein 2, Mice
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