Cited by 993Telomeres, Telomerase, and SenescenceDNA Repair MechanismsDNA and Nucleic Acid Chemistry

Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication

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Sfeir, Agnel, Kosiyatrakul, Settapong T., Hockemeyer, Dirk, MacRae, Sheila L., Karlseder, Jan, Schildkraut, Carl L., de Lange, Titia·2009·Cell

Abstract

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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Crossref · 10.1016/j.cell.2009.06.021

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  • TRF1 can regulate telomere length and also helps DNA replication through telomere repeats.

    “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]

  • Shelterin aids the replication of telomeres.

    “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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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)
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
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
  • 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, 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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