Ilaria RossoCorey Jones-WeinertFrancesca RossielloMatteo CabriniSilvia BrambillascaMuñoz, LeonelLeonelMuñozZeno LavagninoEmanuele MartiniEnzo TedoneMassimiliano Garre’Julio AguadoDario ParazzoliMarina MioneJerry W. ShayCiro MercurioFabrizio d’Adda di Fagagna2025-04-132025-04-132023-11-0410.1038/s41467-023-42831-0https://cris-uv.scimago.es/handle/123456789/1975WOS:001100866900026Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10–15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival. Similar content being viewed by othersacceso abiertoMULTIDISCIPLINARY SCIENCESjournal-article