CSL controls telomere maintenance and genome stability in human dermal fibroblasts.
- Bottoni G Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Katarkar A Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Tassone B Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Ghosh S Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Clocchiatti A Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Goruppi S Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Bordignon P Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
- Jafari P Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
- Tordini F Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, 13900, Biella, Italy.
- Lunardi T Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
- Hoetzenecker W Department of Dermatology, Kepler University Hospital, 4020, Linz, Austria.
- Neel V Department of Dermatology, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Lingner J Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
- Paolo Dotto G Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA. paolo.dotto@unil.ch.
- 2019-08-31
Published in:
- Nature communications. - 2019
Cancer-Associated Fibroblasts
Carcinoma, Squamous Cell
DNA Damage
DNA-Binding Proteins
Fibroblasts
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genomic Instability
HEK293 Cells
Homeostasis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Ku Autoantigen
Membrane Proteins
Molecular Docking Simulation
Mutagenesis
RNA Helicases
Receptors, Notch
Signal Transduction
Skin
Skin Neoplasms
Telomere
Trans-Activators
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/s41467-019-11785-7
- PMID 31467287
- Persistent URL
- https://sonar.ch/global/documents/917
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