Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication

By Agnel Sfeir, Settapong T. Kosiyatrakul, D. Hockemeyer, Sheila L. MacRae, J. Karlseder, C. Schildkraut, T. de Lange. Cell, 2009

1,007 citations recorded by the source corpus.

Summary Mammalian telomeres are associated with shelterin, the telomere specific protein complex that solves the end-protection problem. The telomeric shelterin binding sites, TTAGGG repeats, are maintained by telomerase, which solves the end-replication problem. We report that the TTAGGG repeat arrays of human and mouse telomeres challenge the DNA replication machinery, giving rise to replication-dependent defects that resemble those of the aphidicolin-induced common fragile sites. Conditional gene deletion experiments showed that efficient duplication of telomeric DNA requires the shelterin component TRF1. In the absence of TRF1, telomeres activate the ATR kinase in S phase and show a fragile site phenotype in metaphase. SMARD showed that TRF1 promotes efficient replication of TTAGGG repeats and prevents fork stalling. Two helicases that can remove 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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/3049c23dd9ff0a713ed4847387e2b7c0265a0e03

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Roderick J. O’Sullivan
2. Shahin Rafii
3. C. D. Allis
4. M. Holmes
5. Jeffrey C. Miller
6. de Lange
7. F. Urnov
8. J. Karlseder

In Physiology

1. Roderick J. O’Sullivan
2. de Lange
3. J. Karlseder
4. T. de Lange

Citations in the corpus

• How shelterin solves the telomere end-protection problem. (2010, background): “In the TRF1-deleted cells, ATR activation is dependent on progression through S phase (Sfeir et al. 2009), which is not the case when POT1a/b are removed (Gong and de Lange 2010).”
• Advance Publication by J-STAGE Japanese Journal of Infectious Diseases Isolation of human coronaviruses OC43, HKU1, NL63, and 229E in Yamagata, Japan, using primary human airway epithelium cells cultured by employing an air-liquid interface culture (2020, positive): “Notably, the absence of TRF1 causes replication forkdependent defects, telomeric fusion, and altered genome packaging [29].”
• Distinct factors control histone variant H3.3 localization at specific genomic regions (2010, methodology): “Immunofluorescence and Telomere Fluorescence In Situ Hybridization Telomere fluorescence in situ hybridization (FISH) of ESCs was performed with a peptide nucleic acid TAMRA-TelG telomere probe (Sfeir et al., 2009), and immunofluorescence was performed with a previously described anti-GFP antibody (”
• Telomeres: protecting chromosomes against genome instability (2010, background): “Given these properties, telomeres are thought to resemble fragile sites , and telomeric proteins aid the DNA replication machinery in the accurate duplication of chromosome end”