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

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State: Public
Version: author
License: CC BY 4.0
Serval ID
serval:BIB_3F3ACF15630E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CSL controls telomere maintenance and genome stability in human dermal fibroblasts.
Journal
Nature communications
Author(s)
Bottoni G., Katarkar A., Tassone B., Ghosh S., Clocchiatti A., Goruppi S., Bordignon P., Jafari P., Tordini F., Lunardi T., Hoetzenecker W., Neel V., Lingner J., Dotto G.P.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
29/08/2019
Peer-reviewed
Oui
Volume
10
Number
1
Pages
3884
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish Swiss National Science Foundation
(310030B_176404 “Genomic instability and evolution in cancer stromal cells”), the
European Research Council (26075083), and the NIH (R01AR039190, R01AR064786;
the content does not necessarily represent the official views of the NIH) to GPD
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
17/09/2019 20:44
Last modification date
25/01/2020 6:17
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