Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs
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Published:2023-11-04
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Rosso IlariaORCID, Jones-Weinert CoreyORCID, Rossiello FrancescaORCID, Cabrini Matteo, Brambillasca SilviaORCID, Munoz-Sagredo LeonelORCID, Lavagnino Zeno, Martini EmanueleORCID, Tedone Enzo, Garre’ MassimilianoORCID, Aguado JulioORCID, Parazzoli DarioORCID, Mione MarinaORCID, Shay Jerry W.ORCID, Mercurio CiroORCID, d’Adda di Fagagna FabrizioORCID
Abstract
AbstractAlternative 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.
Funder
Associazione Italiana per la Ricerca sul Cancro Fondazione Telethon Ministero dell'Istruzione, dell'Università e della Ricerca Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica Regione Lombardia
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference107 articles.
1. de Lange, T. Shelterin-mediated telomere protection. Annu Rev. Genet. 52, 223–247 (2018). 2. D’Adda Di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). 3. Herbig, U., Jobling, W. A., Chen, B. P. C., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004). 4. Karlseder, J., Broccoli, D., Yumin, D., Hardy, S. & De Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999). 5. Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell 43, 405–413 (1985).
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