The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination
Abstract
Ku70-Ku80 heterodimers promote the non-homologous end-joining (NHEJ) of DNA breaks and, as shown here, the fusion of dysfunctional telomeres. Paradoxically, this heterodimer is also located at functional mammalian telomeres and interacts with components of shelterin, the protein complex that protects telomeres. To determine whether Ku contributes to telomere protection, we analysed Ku70(-/-) mouse cells. Telomeres of Ku70(-/-) cells had a normal DNA structure and did not activate a DNA damage signal. However, Ku70 repressed exchanges between sister telomeres - a form of homologous recombination implicated in the alternative lengthening of telomeres (ALT) pathway. Sister telomere exchanges occurred at approximately 15% of the chromosome ends when Ku70 and the telomeric protein TRF2 were absent. Combined deficiency of TRF2 and another NHEJ factor, DNA ligase IV, did not elicit this phenotype. Sister telomere exchanges were not elevated at telomeres with functional TRF2, indicating that TRF2 and Ku70 act in parallel to repress recombination. We conclude that mammalian chromosome ends are highly susceptible to homologous recombination, which can endanger cell viability if an unequal exchange generates a critically shortened telomere. Therefore, Ku- and TRF2-mediated repression of homologous recombination is an important aspect of telomere protection.
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“By contrast, when telomeres are compromised through the loss of TRF2, their repair is carried out by c-NHEJ80–82.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [82]
Citations
Cites
Shelterin: the protein complex that shapes and safeguards human telomeres
de Lange, T. (2005) · Genes & Development · doi:10.1101/gad.1346005 · Cited by 3,056
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,917
Mammalian Telomeres End in a Large Duplex Loop
Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., & de Lange, T. (1999) · Cell · doi:10.1016/s0092-8674(00)80760-6 · Cited by 2,447
DNA Damage Foci at Dysfunctional Telomeres
Takai, H., Smogorzewska, A., & de Lange, T. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00542-6 · Cited by 1,409
Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair
Walker, J. R., Corpina, R. A., & Goldberg, J. D. (2001) · Nature · doi:10.1038/35088000 · Cited by 1,216
Telomere maintenance by recombination in human cells
Dunham, M. A., Neumann, A. A., Fasching, C. L., & Reddel, R. R. (2000) · Nature Genetics · doi:10.1038/82586 · Cited by 879
DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion
Celli, G. B., & de Lange, T. (2005) · Nature Cell Biology · doi:10.1038/ncb1275 · Cited by 623
Self-citationT‐loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang
Stansel, R. M., de Lange, T., & Griffith, J. D. (2001) · The EMBO Journal · doi:10.1093/emboj/20.19.5532 · Cited by 562
Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres
Wang, R. C., Smogorzewska, A., & de Lange, T. (2004) · Cell · doi:10.1016/j.cell.2004.10.011 · Cited by 536
Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cellsPreprint
Pierce, A. J., Hu, P., Han, M., Ellis, N. A., & Jasin, M. (2001) · Genes & Development · doi:10.1101/gad.946401 · Cited by 514
Cited by
Sorted by citations
How Shelterin Protects Mammalian Telomeres
Palm, W., & de Lange, T. (2008) · Annual Review of Genetics · doi:10.1146/annurev.genet.41.110306.130350 · Cited by 1,802
The multifaceted roles of PARP1 in DNA repair and chromatin remodelling
Ray Chaudhuri, A., & Nussenzweig, A. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.53 · Cited by 1,786
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170
Alternative lengthening of telomeres: models, mechanisms and implications
Cesare, A. J., & Reddel, R. R. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2763 · Cited by 1,107
Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication
Sfeir, A., Kosiyatrakul, S. T., Hockemeyer, D., MacRae, S. L., Karlseder, J., Schildkraut, C. L., & de Lange, T. (2009) · Cell · doi:10.1016/j.cell.2009.06.021 · Cited by 990
Metadata
- Authors
- Celli, G. B., Denchi, E. L., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- Venue
- Nature Cell Biology
- Published
- 2006-07-16
- Volume
- 8
- Issue
- 8
- Pages
- 885-890
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1990507848
- Cited by
- 320
- References
- 35
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 11 · 2022: 7 · 2021: 8 · 2020: 15 · 2019: 10 · 2018: 13 · 2017: 12 · 2016: 8 · 2015: 15 · 2014: 22 · 2013: 30 · 2012: 17
- FWCI
- 15.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 49046)
- 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
- Ku70, Ku80, telomere protection, homologous recombination, alternative lengthening of telomeres, TRF2, shelterin, non-homologous end joining, DNA ligase IV, telomere dysfunction
- MeSH terms
- Ku Autoantigen, DNA Ligase ATP, Animals, DNA Repair, DNA-Binding Proteins, Microscopy, Fluorescence, Models, Biological, DNA Ligases, Recombination, Genetic, Sister Chromatid Exchange, Immunoblotting, Signal Transduction, Telomere, Protein Serine-Threonine Kinases, Mice, Knockout, Chromosomes, Mammalian, Antigens, Nuclear, Telomeric Repeat Binding Protein 2, Mice, Checkpoint Kinase 2
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