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; G Paolo Dotto

doi:10.1038/s41467-019-11785-7

CSL controls telomere maintenance and genome stability in human dermal fibroblasts

Nat Commun. 2019 Aug 29;10(1):3884. doi: 10.1038/s41467-019-11785-7.

Authors

Giulia Bottoni^{1

2

3}, Atul Katarkar³, Beatrice Tassone³, Soumitra Ghosh³, Andrea Clocchiatti^{1

2}, Sandro Goruppi^{1

2}, Pino Bordignon³, Paris Jafari^{1

3}, Fabio Tordini^{4

5}, Thomas Lunardi⁶, Wolfram Hoetzenecker⁷, Victor Neel⁸, Joachim Lingner⁶, G Paolo Dotto^{9

10

11}

Affiliations

¹ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
² Department of Dermatology, Harvard Medical School, Boston, MA, 02125, USA.
³ Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
⁴ Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, 13900, Biella, Italy.
⁵ Diatech Pharmacogenetics srl, 60035, Jesi, Italy.
⁶ Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
⁷ Department of Dermatology, Kepler University Hospital, 4020, Linz, Austria.
⁸ Department of Dermatology, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁹ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA. paolo.dotto@unil.ch.
¹⁰ Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland. paolo.dotto@unil.ch.
¹¹ International Cancer Prevention Institute, 1066, Epalinges, Switzerland. paolo.dotto@unil.ch.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cancer-Associated Fibroblasts / metabolism*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
DNA Damage
DNA-Binding Proteins
Fibroblasts / metabolism*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genomic Instability*
HEK293 Cells
Homeostasis
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics*
Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
Ku Autoantigen / metabolism
Membrane Proteins
Molecular Docking Simulation
Mutagenesis
RNA Helicases / metabolism
Receptors, Notch / metabolism
Signal Transduction
Skin / metabolism
Skin Neoplasms / genetics
Skin Neoplasms / metabolism
Telomere / metabolism*
Trans-Activators / metabolism

Substances

DNA-Binding Proteins
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Membrane Proteins
RBPJ protein, human
Receptors, Notch
SRPRA protein, human
Trans-Activators
XRCC5 protein, human
RNA Helicases
UPF1 protein, human
Ku Autoantigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding