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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]
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“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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Sorted by citations
Shelterin-Mediated Telomere Protection
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InfluentialThe Ku heterodimer: Function in DNA repair and beyond
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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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InfluentialTRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding
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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 154
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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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FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops
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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
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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 .”
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“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
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“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
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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
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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
“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
Lerner, C. A., Sundar, I. K., & Rahman, I. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.07.026 · Cited by 96
“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
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“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
“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
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 92
“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 85
TRF2 binds branched DNA to safeguard telomere integrity
Schmutz, I., Timashev, L. A., Xie, W., Patel, D. J., & de Lange, T. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3451 · Cited by 93
TRF2-mediated telomere protection is dispensable in pluripotent stem cells
Markiewicz-Potoczny, M., Lobanova, A., Loeb, A. M., Kirak, O., Olbrich, T., Ruiz, S., & Denchi, E. L. (2020) · Nature · doi:10.1038/s41586-020-2959-4 · Cited by 79
Distinct Roles of Meiosis-Specific Cohesin Complexes in Mammalian Spermatogenesis
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Pathways for maintenance of telomeres and common fragile sites during DNA replication stress
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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 85
“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 91
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 83
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 76
“…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 83
Wu, Y., Poulos, R. C., & Reddel, R. R. (2020) · Cancers · doi:10.3390/cancers12102739 · Cited by 73
“POT1 does not appear to be required for t-loop formation [33].”
BackgroundDNA Replication Origins and Fork Progression at Mammalian Telomeres
Higa, M., Fujita, M., & Yoshida, K. (2017) · Genes · doi:10.3390/genes8040112 · Cited by 81
“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
Lee, Y. W., Arora, R., Wischnewski, H., & Azzalin, C. M. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-017-0021-5 · Cited by 78
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Telomere Recognition and Assembly Mechanism of Mammalian Shelterin
Erdel, F., Kratz, K., Willcox, S., Griffith, J. D., Greene, E. C., & de Lange, T. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.005 · Cited by 80
“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
Jack, A., Kim, Y., Strom, A. R., Lee, D. S. W., Williams, B. C., Schaub, J. M., Kellogg, E. H., Finkelstein, I. J., Ferro, L. S., Yıldız, A., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2021.12.017 · Cited by 67
“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
Janoušková, E., Nečasová, I., Pavloušková, J., Zimmermann, M., Hluchý, M., Marini, V., Nováková, M., & Hofr, C. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv097 · Cited by 69
“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).”
Bloom, S. I., Liu, Y., Tucker, J. R., Islam, M. T., Machin, D. R., Abdeahad, H., Thomas, T. G., Bramwell, R. C., Lesniewski, L. A., & Donato, A. J. (2023) · Aging Cell · doi:10.1111/acel.13875 · Cited by 73
The makings of TERRA R-loops at chromosome ends
Fernandes, R. V., Feretzaki, M., & Lingner, J. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1962638 · Cited by 70
“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].”
BackgroundBahrami, A., Bo, S., Jamialahmadi, T., & Sahebkar, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101024 · Cited by 68
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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