Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication

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

Research output: Contribution to journalArticle

533 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)90-103
Number of pages14
JournalCell
Volume138
Issue number1
DOIs
StatePublished - Jul 10 2009

Fingerprint

Telomere
DNA
Aphidicolin
Telomerase
Chromosomes
Machinery
Repair
Phosphotransferases
Genes
Phenotype
Gene Deletion
Defects
Molecules
Metaphase
DNA Replication
S Phase
DNA Repair
DNA Damage
Proteins
Experiments

Keywords

  • DNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sfeir, A., Kosiyatrakul, S. T., Hockemeyer, D., MacRae, S. L., Karlseder, J., Schildkraut, C. L., & de Lange, T. (2009). Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication. Cell, 138(1), 90-103. https://doi.org/10.1016/j.cell.2009.06.021

Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication. / Sfeir, Agnel; Kosiyatrakul, Settapong T.; Hockemeyer, Dirk; MacRae, Sheila L.; Karlseder, Jan; Schildkraut, Carl L.; de Lange, Titia.

In: Cell, Vol. 138, No. 1, 10.07.2009, p. 90-103.

Research output: Contribution to journalArticle

Sfeir, A, Kosiyatrakul, ST, Hockemeyer, D, MacRae, SL, Karlseder, J, Schildkraut, CL & de Lange, T 2009, 'Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication', Cell, vol. 138, no. 1, pp. 90-103. https://doi.org/10.1016/j.cell.2009.06.021
Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL et al. Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication. Cell. 2009 Jul 10;138(1):90-103. https://doi.org/10.1016/j.cell.2009.06.021
Sfeir, Agnel ; Kosiyatrakul, Settapong T. ; Hockemeyer, Dirk ; MacRae, Sheila L. ; Karlseder, Jan ; Schildkraut, Carl L. ; de Lange, Titia. / Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication. In: Cell. 2009 ; Vol. 138, No. 1. pp. 90-103.
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