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

Ilaria Rosso, Corey Jones-Weinert, Francesca Rossiello, Matteo Cabrini, Silvia Brambillasca, Leonel Munoz-Sagredo, Zeno Lavagnino, Emanuele Martini, Enzo Tedone, Massimiliano Garre’, Julio Aguado, Dario Parazzoli, Marina Mione, Jerry W. Shay, Ciro Mercurio and Fabrizio d’Adda di Fagagna ()
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Ilaria Rosso: IFOM ETS - The AIRC Institute of Molecular Oncology
Corey Jones-Weinert: IFOM ETS - The AIRC Institute of Molecular Oncology
Francesca Rossiello: IFOM ETS - The AIRC Institute of Molecular Oncology
Matteo Cabrini: IFOM ETS - The AIRC Institute of Molecular Oncology
Silvia Brambillasca: IFOM ETS - The AIRC Institute of Molecular Oncology (Experimental Therapeutics Program)
Leonel Munoz-Sagredo: Karlsruhe Institute of Technology (KIT)
Zeno Lavagnino: IFOM ETS - The AIRC Institute of Molecular Oncology
Emanuele Martini: IFOM ETS - The AIRC Institute of Molecular Oncology
Enzo Tedone: University of Texas Southwestern Medical Center
Massimiliano Garre’: IFOM ETS - The AIRC Institute of Molecular Oncology
Julio Aguado: IFOM ETS - The AIRC Institute of Molecular Oncology
Dario Parazzoli: IFOM ETS - The AIRC Institute of Molecular Oncology
Marina Mione: University of Trento
Jerry W. Shay: University of Texas Southwestern Medical Center
Ciro Mercurio: IFOM ETS - The AIRC Institute of Molecular Oncology (Experimental Therapeutics Program)
Fabrizio d’Adda di Fagagna: IFOM ETS - The AIRC Institute of Molecular Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41467-023-42831-0

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