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Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication
Open accessAbstract
Telomeres protect chromosome ends through the interaction of telomeric repeats with shelterin, a protein complex that represses DNA damage signaling and DNA repair reactions. The telomeric repeats are maintained by telomerase, which solves the end replication problem. We report that the TTAGGG repeat arrays of mammalian telomeres pose a challenge to the DNA replication machinery, giving rise to replication-dependent defects that resemble those of aphidicolin-induced common fragile sites. Gene deletion experiments showed that efficient duplication of telomeres requires the shelterin component TRF1. Without TRF1, telomeres activate the ATR kinase in S phase and show a fragile-site phenotype in metaphase. Single-molecule analysis of replicating telomeres showed that TRF1 promotes efficient replication of TTAGGG repeats and prevents fork stalling. Two helicases implicated in the removal of G4 DNA structures, BLM and RTEL1, were required to repress the fragile-telomere phenotype. These results identify a second telomere replication problem that is solved by the shelterin component TRF1.
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“TRF1 can serve to modulate telomere length, but it also serves to facilitate DNA replication through the telomere repeats, which acts as fragile DNA sites (5)(6)(7).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [7]
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“The shelterin protein complex protects telomeres, facilitates replication and controls access of telomerase.”
From Telomeres and telomerase in cancer (2010) · cites this paper as Sfeir,A. et al. (2009)
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Metadata
- Authors
- Sfeir, A., Kosiyatrakul, S. T., Hockemeyer, D., MacRae, S. L., Karlseder, J., Schildkraut, C. L., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- Albert Einstein College of Medicine (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 138
- Issue
- 1
- Pages
- 90-103
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2723738
- OpenAlex
- W2161232591
- Cited by
- 990
- References
- 73
- Citations by year
- 2026: 28 · 2025: 50 · 2024: 44 · 2023: 60 · 2022: 42 · 2021: 60 · 2020: 83 · 2019: 59 · 2018: 57 · 2017: 54 · 2016: 61 · 2015: 66 · 2014: 73 · 2013: 67 · 2012: 67
- FWCI
- 41.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1477 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Susan G. Komen
- National Institutes of Health
- U.S. Bureau of Land Management
- National Institute on Aging (R01AG016642)
- National Cancer Institute (R01CA076027)
- National Institute of General Medical Sciences (R37GM049046)
- 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, TRF1, shelterin, fragile sites, DNA replication, TTAGGG repeats, ATR kinase, BLM helicase, RTEL1, telomere maintenance, mammalian cells
- MeSH terms
- Animals, DNA Replication, Humans, Metaphase, Aphidicolin, Telomere, Chromosomes, Mammalian, Telomeric Repeat Binding Protein 1, Chromosome Fragile Sites, Mice
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