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 that facilitates the formation of telomere loops to hide the telomere end, thus protecting chromosome ends from DNA break signaling pathways.
“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]
TRF2 overexpression delays replicative senescence onset, indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.
“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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BackgroundStructural biology of telomeres and telomerase
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“At telomeres, shelterin proteins mediate distinct functions: TRF2 is required for T-loop formation and maintenance (Doksani et al., 2013), and for repression of ATM-mediated DNA damage response (DDR) as well as nonhomologous end joining (NHEJ) (Karlseder et al., 2004; Denchi and de Lange, 2007;…”
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Complex interactions between the DNA-damage response and mammalian telomeres
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“While the ex vivo electron microscopy and super-resolution microscopy used to visualize t-loops do not directly report on numbers of t-loops in vivo, it has been estimated that a majority of telomeres in human cells form t-loops at any time [79,80].”
BackgroundLive Cell Imaging Reveals the Dynamics of Telomerase Recruitment to Telomeres
Schmidt, J. C., Zaug, A. J., & Cech, T. R. (2016) · Cell · doi:10.1016/j.cell.2016.07.033 · Cited by 177 · see citing works
“The availability of the 30 overhang is likely regulated by telomeric structure, for instance the formation of T-loops, whether DNA replication has been completed at the telomere, and the signaling state of the telomere (Doksani et al., 2013; Lee et al., 2015; Tong et al., 2015).”
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Telomeropathies: An emerging spectrum disorder
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“In the absence of RTEL1, the T-loop is excised by the SLX4 nuclease, which causes rapid telomere loss (Vannier et al., 2012).”
InfluentialTRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding
Sarek, G., Vannier, J., Panier, S., Petrini, J. H. J., & Boulton, S. J. (2015) · Molecular Cell · doi:10.1016/j.molcel.2014.12.024 · Cited by 175 · see citing works
“TRF2 is also essential for t-loop formation in vivo (Doksani et al., 2013), which likely contributes to its key role in end protection.”
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Shelterin Protects Chromosome Ends by Compacting Telomeric Chromatin
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“Wild-type (WT) TRF2 was removed from telomeres by overexpressing a dominant-negative mutant (TRF2) (Doksani et al., 2013).”
BackgroundMethodInfluentialStop pulling my strings — what telomeres taught us about the DNA damage response
Denchi, E. L., & Sfeir, A. J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.43 · Cited by 166 · see citing works
The molecular genetics of the telomere biology disorders
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The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability
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“Electron microscopy and super-resolution fluorescence microscopy studies revealed that telomeric DNA can fold into higher-order structures in which the single-stranded overhang invades the homologous double-stranded region, forming a telomeric loop (T-loop) [9,10].”
BackgroundAlternative Lengthening of Telomeres: DNA Repair Pathways Converge
Sobinoff, A. P., & Pickett, H. A. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.09.003 · Cited by 166 · see citing works
BLM helicase facilitates telomere replication during leading strand synthesis of telomeres
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Impact of oxidative stress on telomere biology
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“This higher-order telomeric DNA structure is believed to play a key role in telomere protection (Doksani et al., 2013) and has been proposed to be linked to the ability of TRF2 to stimulate invasion of duplex telomeric DNA by a homologous single strand (Amiard et al.”
MethodInfluentialTelomere-associated aging disorders
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“In a recent study applying 3D-STORM, FISH detected telomeres appeared as ovoid clusters with an average diameter of 180 nm.(62) Although SIM does not offer the localization accuracy of STORM,(63) highresolution microscopy of telomeres using the dCas9 labeling system revealed a consistent morphology to the above-mentio…”
ResultRevisiting Telomere Shortening in Cancer
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FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres
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“For example, the telomeric G-strand overhang folds back, invades the internal double-stranded regions of telomere, and forms the telomeric loop (T-loop) as well as the displacement-loop (D-loop) (19, 20).”
BackgroundTRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends
Wood, A. M., Danielsen, J. M. R., Lucas, C. A., Rice, E. L., Scalzo, D., Shimi, T., Goldman, R. D., Smith, E. D., Beau, M. M. L., & Kosak, S. T. (2014) · Nature Communications · doi:10.1038/ncomms6467 · Cited by 142 · see citing works
“Previous studies investigating t-loop structures in mammalian cells did not observe the ITL described here, likely because these studies specifically removed non-telomeric DNA from analysis 7,12 or specifically visualised only telomeric DNA 10 .”
Rai, R., Chen, Y., Lei, M., & Chang, S. S. (2016) · Nature Communications · doi:10.1038/ncomms10881 · Cited by 136 · see citing works
RTEL1: functions of a disease-associated helicase
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The Role of Double-Strand Break Repair Pathways at Functional and Dysfunctional TelomeresPreprint
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Self-citationNuRD–ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination
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Telomere Loop Dynamics in Chromosome End Protection
Ly, D. V., Low, R. R. J., Frölich, S., Bartolec, T. K., Kafer, G. R., Pickett, H. A., Gaus, K., & Cesare, A. J. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.06.025 · Cited by 128 · see citing works
TERRA-Reinforced Association of LSD1 with MRE11 Promotes Processing of Uncapped Telomeres
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“Consistent with this notion, t loop formation depends on TRF2 (Doksani et al., 2013).”
BackgroundAeby, E., Ahmed, W., Redon, S., Simanis, V., & Lingner, J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.071 · Cited by 123 · see citing works
FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops
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Replicating through telomeres: a means to an end
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Structure and function of the telomeric CST complex
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“Shelterinalso capstheends of chromosomes by facilitating T-loop formation and by sequestering the single-stranded DNA portion of the telomere [12,13].”
BackgroundControl of telomerase action at human telomeres
Hockemeyer, D. F., & Collins, K. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3083 · Cited by 118 · see citing works
Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases
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“The single-stranded 3’ over-hang loops back and invades double-stranded telomeric DNA in a TRF2-dependent manner 11,12 .”
BackgroundFrom single molecules to life: microscopy at the nanoscale
Turkowyd, B., Virant, D., & Endesfelder, U. (2016) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-016-9781-8 · Cited by 114 · see citing works
“In super-resolution applications, it is a powerful tool for studying chromatin structure and organization, gene location [148, 149], RNA localization and quantification [148], telomere structure [150], etc.”
MethodStabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe
Margalef, P., Kotsantis, P., Borel, V., Bellelli, R., Panier, S., & Boulton, S. J. (2017) · Cell · doi:10.1016/j.cell.2017.11.047 · Cited by 109 · see citing works
“One way that TRF2 protects chromosome ends is by promoting the formation of t-loops at telomeres, which form when the 30 single-stranded telomeric G-rich overhang invades into internal telomeric repeats to form a lariat-like structure (Doksani et al., 2013; Griffith et al., 1999).”
BackgroundChemistry of Photosensitive Fluorophores for Single-Molecule Localization Microscopy
Jradi, F. M., & Lavis, L. D. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00197 · Cited by 113 · see citing works
Telomeres, Telomerase and Ageing
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Telomere Replication: Solving Multiple End Replication Problems
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A balance between elongation and trimming regulates telomere stability in stem cells
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TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity
Mei, Y., Deng, Z., Vladimirova, O. V., Gulve, N., Johnson, F. B., Drosopoulos, W. C., Schildkraut, C. L., & Lieberman, P. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-82406-x · Cited by 104 · see citing works
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“For example, the telomeric G-rich strand overhang folds back, invades the internal doublestranded regions of telomeres, and forms the telomeric-loop (T-loop) as well as the displacement-loop (D-loop) (Griffith et al., 1999; Doksani et al., 2013).”
BackgroundDoksani, Y., & de Lange, T. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.008 · Cited by 101 · see citing works
“TRF2 is required for formation/maintenance of t-loops, which have been proposed to sequester the chromosome end via strand invasion of the 30 telomeric overhang into the duplex telomeric repeats, thus making the telomere terminus inaccessible to the initiating factors of ATM signaling and classical c-NHEJ, MRN, and Ku…”
Self-citationMitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD
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“Telomere loop formation by TRF2 protects its ends from recognition by DNA damage pathways (Doksani et al., 2013).”
BackgroundTelomerase in Cancer: Function, Regulation, and Clinical Translation
Robinson, N. J., & Schiemann, W. P. (2022) · Cancers · doi:10.3390/cancers14030808 · Cited by 94 · see citing works
“Moreover, TRF1 and TRF2 binding protects against illicit DNA repair by shielding chromosome ends from DNA damage recognition [24] and facilitating telomere loop (t-loop) formation, whereby obligate 3′ singlestranded telomere overhangs are sequestered within triplex DNA structures [25].”
BackgroundAn R-loop-initiated CSB–RAD52–POLD3 pathway suppresses ROS-induced telomeric DNA breaks
Tan, J. J., Duan, M.-H., Yadav, T., Phoon, L. Y., Wang, X., Zhang, J., Zou, L., & Lan, L. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1114 · Cited by 91 · see citing works
“TRF2 plays an essential role in the maintenance of telomere integrity, and it promotes invasion of G-rich ssDNA overhang into the telomere duplex DNA to form t-loops (23).”
BackgroundBRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
Vohhodina, J., Goehring, L. J., Liu, B., Kong, Q., Botchkarev, V. V., Huynh, M. A., Liu, Z., Abderazzaq, F. O., Clark, A. P., Ficarro, S. B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23716-6 · Cited by 91 · see citing works
From “Cellular” RNA to “Smart” RNA: Multiple Roles of RNA in Genome Stability and Beyond
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CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle
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“This 3′-overhang is proposed to loop back and invade into the doublestranded telomeric repeat DNA to form a so-called T-loop, which resembles the D-loop generated as an intermediate during homologous recombination [2, 3].”
BackgroundTelomeres: Implications for Cancer Development
Bernal, A., & Tusell, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010294 · Cited by 86 · see citing works
“Several studies point out the involvement of TRF2 with the generation of DNA loops in vitro [21–23], as lariat structures are not observed when TRF2 is absent [23].”
BackgroundAlternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends
Hoang, S. M., & O’Sullivan, R. J. (2020) · Trends in cancer · doi:10.1016/j.trecan.2019.12.009 · Cited by 83 · see citing works
TRF2 binds branched DNA to safeguard telomere integrity
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TRF2-mediated telomere protection is dispensable in pluripotent stem cells
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Distinct Roles of Meiosis-Specific Cohesin Complexes in Mammalian Spermatogenesis
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“The G-rich 30 terminating strand forms a ssDNA overhang that is also necessary for telomere maintenance because it can invade into the double-stranded telomeric DNA to form a protective structure called the t-loop [64,65].”
BackgroundHigh resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer
Schmidt, T. T., Tyer, C., Rughani, P., Haggblom, C., Jones, J. R., Dai, X., Frazer, K. A., Gage, F. H., Juul, S., Hickey, S. F., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48917-7 · Cited by 79 · see citing works
“6b), but also a more homogenous telomere length distribution (Supplementary Tables 3, 4).”
InfluentialCondensate interfacial forces reposition DNA loci and probe chromatin viscoelasticity
Strom, A. R., Kim, Y., Zhao, H., Chang, Y.-C., Orlovsky, N. D., Košmrlj, A., Storm, C., & Brangwynne, C. P. (2024) · Cell · doi:10.1016/j.cell.2024.07.034 · Cited by 79 · see citing works
Telomere Maintenance Mechanisms in Cancer: Clinical Implications
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“Visualization of tloops by super-resolution light microscopy has demonstrated that the point of invasion can be located at almost any point along the duplex DNA, resulting in t-loops of highly variable sizes [13].”
BackgroundThe Response to DNA Damage at Telomeric Repeats and Its Consequences for Telomere Function
Doksani, Y. (2019) · Genes · doi:10.3390/genes10040318 · Cited by 77 · see citing works
Self-citationPRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerasePreprint
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The BUB3-BUB1 Complex Promotes Telomere DNA Replication
Li, F., Kim, H., Ji, Z., Zhang, T., Chen, B., Ge, Y., Hu, Y., Feng, X., Han, X., Xu, H., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.03.032 · Cited by 74 · see citing works
“…in telomere protection and T-loop maintenance likely contributes to its function in promoting telomere closed state, which are difficult to resolve during telomere replication (Benarroch-Popivker et al., 2016; Cesare and Karlseder, 2012; Doksani et al., 2013; Okamoto et al., 2013; Stansel Mol Cell.”
BackgroundInfluentialBring It to an End: Does Telomeres Size Matter?
Laberthonnìère, C., Magdinier, F., & Robin, J. D. (2019) · Cells · doi:10.3390/cells8010030 · Cited by 78 · see citing works
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“POT1 does not appear to be required for t-loop formation [33].”
BackgroundDNA Replication Origins and Fork Progression at Mammalian Telomeres
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“However, TRF2 is also essential for the assembly of the T-loop [7,8,155].”
BackgroundTRF1 participates in chromosome end protection by averting TRF2-dependent telomeric R loops
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Telomere Recognition and Assembly Mechanism of Mammalian Shelterin
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“Mammalian telomeres contain the six-subunit protein complex shelterin (de Lange, 2005), which prevents recognition of chromosome ends as DNA breaks, in part by forming the t-loop structure (Doksani et al., 2013; Griffith et al., 1999).”
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Compartmentalization of telomeres through DNA-scaffolded phase separation
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“The tloop model provides an explanation for how shelterin sequesters the chromosome ends from the ATM and NHEJ pathways (Doksani et al., 2013; Griffith et al., 1999).”
Human Rap1 modulates TRF2 attraction to telomeric DNA
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“One possible explanation surfaced from the finding that TRF2 alters the spatial arrangement of telomeric DNA by formation of specific telomeric loop structures (t-loops) (6,7).”
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The makings of TERRA R-loops at chromosome ends
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“In T-loops, the telomeric 3ʹ overhang is tucked into the double-stranded part of the telomere, base pairing with the complementary 5ʹCCCTAA-3ʹ repeats [8].”
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- 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
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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