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

Author

Listed:
  • Ilaria Rosso

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Corey Jones-Weinert

    (IFOM ETS - The AIRC Institute of Molecular Oncology
    The Salk Institute for Biological Studies)

  • 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)
    Universidad de Valparaiso)

  • Zeno Lavagnino

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Emanuele Martini

    (IFOM ETS - The AIRC Institute of Molecular Oncology
    Università degli Studi di Milano)

  • Enzo Tedone

    (University of Texas Southwestern Medical Center)

  • Massimiliano Garre’

    (IFOM ETS - The AIRC Institute of Molecular Oncology
    RCSI, Royal College of Surgeons in Ireland, Department of Chemistry)

  • Julio Aguado

    (IFOM ETS - The AIRC Institute of Molecular Oncology
    The University of Queensland)

  • 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
    Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”)

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.

Suggested Citation

  • Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42831-0
    DOI: 10.1038/s41467-023-42831-0
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