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The DNA damage response (DDR) arrests cell-cycle progression until damage is removed. DNA damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously-induced persistent DDR markers are associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break (DSB) next to telomeric sequences resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a DSB induces persistent DNA damage and DDR. Linear telomeric DNA, but not circular or scrambled DNA, induces a prolonged checkpoint in normal cells. In terminally-differentiated tissues of old primates, DDR markers accumulate at telomeres which are not critically short. We propose that linear genomes are not uniformly 12Correspondence should be addressed to Fabrizio, d’Adda di Fagagna IFOM Foundation – The FIRC Institute of Molecular Oncology Foundation, via Adamello 16, 20139 Milan, Italy, Tel. +39 02 574303.227, Fax +39 02 574303.231, fabrizio.dadda@ifomieo-campus.it. 8Present Address: TTFactor Srl, Milan, Italy. 9Present Address: Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy. 10Present Address: Fresenius Medical Care, Turin, Italy. 11These authors contributed equally Author Contributions F.R. generated and assembled data in Figs. 5a–c, 5e–f, 5h–i, 7a–c, 8d, S1b–c, S3b, S4c, S5, S6, S7b–c, S8a; M.C. and M.P.L. generated data in Fig. 6; S.B. performed the microinjection experiments; D.C. performed the analysis of sequencing data and generated data in Figs. 3a–b; J. M. K. generated data in Figs. 8e and S8b; G.B. contributed to the pre-processing and analysis of sequencing data in Figs. 3a–b; M.D. provided technical assistance; V.M. generated data in Figs. 5d and 5g and provided technical assistance; C.M.B. provided irradiated mice brain sections; U.H. provided baboons sections and edited the ms; M.F. generated and assembled data of all remaining figures, performed ChIP assays in mammalian cells, contributed to experimental design and ms writing; F.d’A.d.F. planned and supervised the project and wrote the ms. The authors declare no conflict of interests. NIH Public Access Author Manuscript Nat Cell Biol. Author manuscript; available in PMC 2013 July 22. Published in final edited form as: Nat Cell Biol. ; 14(4): 355–365. doi:10.1038/ncb2466. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript reparable and telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.

Erratum: Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation