The ends of linear eukaryotic chromosomes are protected by telomeres, which serve to ensure proper chromosome replication and to prevent spurious recombination at chromosome ends. In this study, we show by single cell analysis that in the absence of telomerase, a single short telomere is sufficient to induce the recruitment of checkpoint and recombination proteins. Notably, a DNA damage response at eroded telomeres starts many generations before senescence and is characterized by the recruitment of Cdc13 (cell division cycle 13), replication protein A, DNA damage checkpoint proteins and the DNA repair protein Rad52 into a single focus. Moreover, we show that eroded telomeres, although remaining at the nuclear periphery, move to the nuclear pore complex. Our results link the DNA damage response at eroded telomeres to changes in subnuclear localization and suggest the existence of collapsed replication forks at eroded telomeres.
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We thank members of the Géli, Gilson and Lisby laboratories for helpful discussions concerning this work, A. Nicolas, X. Zhao, R. Rothstein, B. Palancade, V. Lundblad and R. Wellinger for sharing reagents and for fruitful discussions, S. Larose and R. Wellinger, who engineered the pTet-off-TLC1 construct, and S. Brill for the anti-RPA antibody. This work was supported by The Danish Agency for Science, Technology and Innovation (M.L.), the Villum Kann Rasmussen Foundation (M.L.), the Deutscher Akademischer Austausch Dienst (S.M.G.) and the Lundbeck Foundation (N.E.B.). The Agence Nationale de la Recherche (ANR programme blanc) and the Ligue Nationale Contre le Cancer (LNCC, équipes labelisées) supported V.G. and E.G. laboratories; B.K. is a recipient of a fellowship from the LNNC and P.A. is supported by the Lebanese National council for Scientific Research (CNRSL) and the Association pour la Recherche sur le Cancer (ARC).
The authors declare no competing financial interests.
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Khadaroo, B., Teixeira, M., Luciano, P. et al. The DNA damage response at eroded telomeres and tethering to the nuclear pore complex. Nat Cell Biol 11, 980–987 (2009). https://doi.org/10.1038/ncb1910
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