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 is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.
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We thank V. Dall’Olio and L. Tizzoni from IFOM RT–PCR Unit, A. Oldani and all the IFOM Imaging Unit, L. Rotta from IFOM Microarray and NGS Unit, IFOM Cell Biology Unit for support; V. Boccardi for discussions; P. Baumann, T. F. Halazonetis, T. Weinert, D. E. Gottschling, E. Soutoglou, E. Gilson, P. Jeggo, A. Musacchio and S. Minucci for sharing reagents; O. Le for mouse brain tissue sectioning and all F.d’A.d.F. laboratory members for discussions. F.d’A.d.F.’s laboratory is supported by FIRC (Fondazione Italiana per la Ricerca sul Cancro), AIRC (Associazione Italiana per la Ricerca sul Cancro; grant number 8866), European Union (GENINCA, contract number 202230), HFSP (Human Frontier Science Program), AICR (Association for International Cancer Research), EMBO Young Investigator Program and Telethon. M.P.L.’s laboratory is supported by AIRC (grant number 11407), Cofinanziamento 2008 MIUR/Università di Milano-Bicocca and the European Union. C.M.B. is supported by a grant from the Canadian Institute of Health Research (number IAO-79317). U.H. is supported by a New Scholar Award from the Ellison Medical Foundation (AG-NS-0387-07) and by a grant (R01CA136533) from the National Cancer Institute.
The authors declare no competing financial interests.
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Fumagalli, M., Rossiello, F., Clerici, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14, 355–365 (2012). https://doi.org/10.1038/ncb2466
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