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CSL controls telomere maintenance and genome stability in human dermal fibroblasts

Author

Listed:
  • Giulia Bottoni

    (Massachusetts General Hospital
    Harvard Medical School
    University of Lausanne)

  • Atul Katarkar

    (University of Lausanne)

  • Beatrice Tassone

    (University of Lausanne)

  • Soumitra Ghosh

    (University of Lausanne)

  • Andrea Clocchiatti

    (Massachusetts General Hospital
    Harvard Medical School)

  • Sandro Goruppi

    (Massachusetts General Hospital
    Harvard Medical School)

  • Pino Bordignon

    (University of Lausanne)

  • Paris Jafari

    (Massachusetts General Hospital
    University of Lausanne)

  • Fabio Tordini

    (Edo and Elvo Tempia Valenta Foundation
    Diatech Pharmacogenetics srl)

  • Thomas Lunardi

    (Ecole Polytechnique Fédérale de Lausanne)

  • Wolfram Hoetzenecker

    (Department of Dermatology, Kepler University Hospital)

  • Victor Neel

    (Massachusetts General Hospital)

  • Joachim Lingner

    (Ecole Polytechnique Fédérale de Lausanne)

  • G. Paolo Dotto

    (Massachusetts General Hospital
    University of Lausanne
    International Cancer Prevention Institute)

Abstract

Genomic instability is a hallmark of cancer. Whether it also occurs in Cancer Associated Fibroblasts (CAFs) remains to be carefully investigated. Loss of CSL/RBP-Jκ, the effector of canonical NOTCH signaling with intrinsic transcription repressive function, causes conversion of dermal fibroblasts into CAFs. Here, we find that CSL down-modulation triggers DNA damage, telomere loss and chromosome end fusions that also occur in skin Squamous Cell Carcinoma (SCC)-associated CAFs, in which CSL is decreased. Separately from its role in transcription, we show that CSL is part of a multiprotein telomere protective complex, binding directly and with high affinity to telomeric DNA as well as to UPF1 and Ku70/Ku80 proteins and being required for their telomere association. Taken together, the findings point to a central role of CSL in telomere homeostasis with important implications for genomic instability of cancer stromal cells and beyond.

Suggested Citation

  • Giulia Bottoni & Atul Katarkar & Beatrice Tassone & Soumitra Ghosh & Andrea Clocchiatti & Sandro Goruppi & Pino Bordignon & Paris Jafari & Fabio Tordini & Thomas Lunardi & Wolfram Hoetzenecker & Victo, 2019. "CSL controls telomere maintenance and genome stability in human dermal fibroblasts," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11785-7
    DOI: 10.1038/s41467-019-11785-7
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    Cited by:

    1. Soumitra Ghosh & Jovan Isma & Paola Ostano & Luigi Mazzeo & Annagiada Toniolo & Monalisa Das & Joni R. White & Christian Simon & G. Paolo Dotto, 2024. "Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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