CSL controls telomere maintenance and genome stability in human dermal fibroblasts

Giulia Bottoni, Atul Katarkar, Beatrice Tassone, Soumitra Ghosh, Andrea Clocchiatti, Sandro Goruppi, Pino Bordignon, Paris Jafari, Fabio Tordini, Thomas Lunardi, Wolfram Hoetzenecker, Victor Neel, Joachim Lingner and G. Paolo Dotto ()
Additional contact information
Giulia Bottoni: Massachusetts General Hospital
Atul Katarkar: University of Lausanne
Beatrice Tassone: University of Lausanne
Soumitra Ghosh: University of Lausanne
Andrea Clocchiatti: Massachusetts General Hospital
Sandro Goruppi: Massachusetts General Hospital
Pino Bordignon: University of Lausanne
Paris Jafari: Massachusetts General Hospital
Fabio Tordini: Edo and Elvo Tempia Valenta Foundation
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

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11785-7

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