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

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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

DOI 10.1016/j.cell.2009.06.021PMC PMC2723738

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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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BIOGENESIS OF TELOMERASE RNA IN FISSION YEAST
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Analysis of the Role of TRF1 Phosphorylation and TRF1 Domain Structure in Alternative Lengthening of Telomeres Activity
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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)
ORCID: Sfeir, Agnel
Hockemeyer, Dirk
MacRae, Sheila L.
Karlseder, Jan
Venue: Cell
Publisher: Elsevier BV
Published: 2009-07
Volume: 138
Issue: 1
Pages: 90-103
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2009.06.021
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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Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication

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