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

CSL controls telomere maintenance and genome stability in human dermal fibroblasts.

Author information

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.

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