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.


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


  • 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