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Mammalian Telomeres End in a Large Duplex Loop
Open accessAbstract
Mammalian telomeres contain a duplex array of telomeric repeats bound to the telomeric repeat-binding factors TRF1 and TRF2. Inhibition of TRF2 results in immediate deprotection of chromosome ends, manifested by loss of the telomeric 3' overhang, activation of p53, and end-to-end chromosome fusions. Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro. Electron microscopy analysis of psoralen cross-linked telomeric DNA purified from human and mouse cells revealed abundant large t loops with a size distribution consistent with their telomeric origin. Binding of TRF1 and single strand binding protein suggested that t loops are formed by invasion of the 3' telomeric overhang into the duplex telomeric repeat array. T loops may provide a general mechanism for the protection and replication of telomeres.
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In the citing paper
“It has been hypothesized that with the progressive loss of telomere repeats with cell division due to the “end-replication problem”, shelterin components may be displaced from telomere regions and subsequently destabilize the abovementioned t-loop conformation (Griffith et al., 1999). This results in the exposure of the telomere end, which becomes recognized by the DNA repair machinery as a double”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Griffith et al., 1999
In the citing paper
“The overhang is thought to bind to one of the double-stranded DNA regions and facilitate the formation of the t-loop structure (Griffith et al., 1999).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Griffith et al., 1999
In the citing paper
“It is thought that with each cell division, telomere shortening precipitates the loss of “shelterin” components and the destabilization of the t-loop conformation, resulting in exposure of the telomere end (Griffith et al., 1999).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Griffith et al., 1999
In the citing paper
“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 [87]
In the citing paper
“The single-stranded overhang can fold back on the double-stranded telomere in a lariat structure termed the t-loop, which serves to sequester the chromosome terminus (2).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [2]
In the citing paper
“Telomeres can exist in a looped conformation, termed the t-loop, in which the single-stranded overhang folds back on the double-stranded telomere to sequester the end.”
From Telomeres and telomerase in cancer (2010) · cites this paper as Griffith,J.D. et al. (1999)
In the citing paper
“This preference for the t loop junction was not observed for TRF1 which displayed extensive binding along the duplex telomeric DNA even when the DNA was in the t loop configuration.”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [21]
In the citing paper
“However, electron microscope analysis indicated that when TRF2 is associated with telomeric DNA in the t loop configuration, it is preferentially positioned on or near the t loop junction rather than along the telomeric tract (21).”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [21]
In the citing paper
“TRF2 was found to induce the invasion of the 3′ single-stranded TTAGGG repeat tail into duplex telomeric DNA, forming t loops in vitro (21; R. Stansel, T. de Lange, and J. D. Griffith, unpublished data).”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [21]
In the citing paper
“Rap1p and TRF2 display intriguing similarities in biochemical activities that are relevant to telomere looping (17, 18, 21).”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [21]
In the citing paper
“HeLal.2.11 has telomeres of approximately 15 to 40 kb (21), whereas HeLall has shorter telomeres ranging from 3 to 6.5 kb (6 kb median) (39).”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [21]
In the citing paper
“Analysis of telomeres from a diverse array of organisms revealed that the telomere 3′ single-stranded overhang can invade the double-stranded telomeric tracts, displacing the homologous strand of the same telomere. Consequently, a telomere forms a lasso-like structure, termed the ‘t-loop’, with a displacement (D) loop at the invasion site12, 13”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [12]
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Metadata
- Authors
- Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., & de Lange, T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Rockefeller University (US)
- Corresponding author
- Griffith, Jack D
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1999-05
- Volume
- 97
- Issue
- 4
- Pages
- 503-514
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2032407757
- Cited by
- 2,447
- References
- 14
- Citations by year
- 2026: 26 · 2025: 43 · 2024: 71 · 2023: 63 · 2022: 61 · 2021: 82 · 2020: 74 · 2019: 77 · 2018: 69 · 2017: 60 · 2016: 84 · 2015: 88 · 2014: 96 · 2013: 97 · 2012: 80
- FWCI
- 62.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Cancer Institute (CA19043)
- National Institute of General Medical Sciences (GM 49046, GM-31819, R01GM031819)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- telomeres, T-loop, TRF2, TRF1, telomeric overhangs, chromosome end protection, telomere replication, single-stranded DNA binding protein, chromosome fusion, p53 activation, DNA loop formation
- MeSH terms
- Animals, Cross-Linking Reagents, DNA, DNA-Binding Proteins, HeLa Cells, Humans, Mammals, Models, Molecular, Nucleic Acid Heteroduplexes, Recombinant Fusion Proteins, Telomere, Telomeric Repeat Binding Protein 1, Telomeric Repeat Binding Protein 2, Mice
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