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Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs

Rosso, Ilaria; Jones-Weinert, Corey; Rossiello, Francesca; Cabrini, Matteo; Brambillasca, Silvia; Munoz-Sagredo, Leonel 1; Lavagnino, Zeno; Martini, Emanuele; Tedone, Enzo; Garre’, Massimiliano; Aguado, Julio; Parazzoli, Dario; Mione, Marina; Shay, Jerry W.; Mercurio, Ciro; d’Adda di Fagagna, Fabrizio
1 Institut für Biologische und Chemische Systeme (IBCS), Karlsruher Institut für Technologie (KIT)

Abstract:

Alternative 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 engage-
ment 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.


Verlagsausgabe §
DOI: 10.5445/IR/1000164637
Veröffentlicht am 28.11.2023
Originalveröffentlichung
DOI: 10.1038/s41467-023-42831-0
Scopus
Zitationen: 2
Web of Science
Zitationen: 2
Dimensions
Zitationen: 2
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische und Chemische Systeme (IBCS)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2023
Sprache Englisch
Identifikator ISSN: 2041-1723
KITopen-ID: 1000164637
HGF-Programm 43.33.11 (POF IV, LK 01) Adaptive and Bioinstructive Materials Systems
Erschienen in Nature Communications
Verlag Nature Research
Band 14
Seiten Art.-Nr.: 7086
Vorab online veröffentlicht am 04.11.2023
Nachgewiesen in Scopus
Web of Science
Dimensions
Globale Ziele für nachhaltige Entwicklung Ziel 3 – Gesundheit und Wohlergehen
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