title: Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation.
abstract: 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.
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossiello
authors.forename: Michela
authors.initials: M
authors.lastname: Clerici
authors.forename: Sara
authors.initials: S
authors.lastname: Barozzi
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Kaplunov
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bucci
authors.forename: Miryana
authors.initials: M
authors.lastname: Dobreva
authors.forename: Valentina
authors.initials: V
authors.lastname: Matti
authors.forename: Christian M
authors.initials: CM
authors.lastname: Beausejour
authors.forename: Utz
authors.initials: U
authors.lastname: Herbig
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Longhese
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
chemical_list: C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2