CSL controls telomere maintenance and genome stability in human dermal fibroblasts.
Cancer-Associated Fibroblasts
/ metabolism
Carcinoma, Squamous Cell
/ genetics
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
Ku Autoantigen
/ metabolism
Membrane Proteins
Molecular Docking Simulation
Mutagenesis
RNA Helicases
/ metabolism
Receptors, Notch
/ metabolism
Signal Transduction
Skin
/ metabolism
Skin Neoplasms
/ genetics
Telomere
/ metabolism
Trans-Activators
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 08 2019
29 08 2019
Historique:
received:
10
05
2019
accepted:
31
07
2019
entrez:
31
8
2019
pubmed:
31
8
2019
medline:
7
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31467287
doi: 10.1038/s41467-019-11785-7
pii: 10.1038/s41467-019-11785-7
pmc: PMC6715699
doi:
Substances chimiques
DNA-Binding Proteins
0
Immunoglobulin J Recombination Signal Sequence-Binding Protein
0
Membrane Proteins
0
RBPJ protein, human
0
Receptors, Notch
0
SRPRA protein, human
0
Trans-Activators
0
XRCC5 protein, human
EC 3.6.4.12
RNA Helicases
EC 3.6.4.13
UPF1 protein, human
EC 3.6.4.13
Ku Autoantigen
EC 4.2.99.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3884Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR039190
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR064786
Pays : United States
Références
Genes Dev. 2008 Jan 15;22(2):125-40
pubmed: 18198332
Mutat Res Rev Mutat Res. 2015 Jan-Mar;763:15-29
pubmed: 25795113
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14715-6
pubmed: 21873209
J Biol Chem. 2012 Oct 12;287(42):34904-16
pubmed: 22915591
Nat Rev Mol Cell Biol. 2017 Mar;18(3):175-186
pubmed: 28096526
Br J Cancer. 2008 Jul 8;99(1):118-25
pubmed: 18594537
J Clin Invest. 2018 Dec 3;128(12):5531-5548
pubmed: 30395538
Nat Struct Mol Biol. 2015 Nov;22(11):859-66
pubmed: 26581520
Cell. 2006 Mar 10;124(5):985-96
pubmed: 16530045
Nat Rev Genet. 2008 Sep;9(9):699-712
pubmed: 18679436
Nucleic Acids Res. 1999 Sep 1;27(17):3494-502
pubmed: 10446239
EMBO J. 2011 Jan 5;30(1):43-56
pubmed: 21102556
Structure. 2014 Jan 7;22(1):70-81
pubmed: 24290140
Nat Rev Cancer. 2008 Dec;8(12):957-67
pubmed: 19005492
Int J Cancer. 2006 Sep 15;119(6):1345-53
pubmed: 16642473
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Curr Biol. 2006 Feb 21;16(4):433-9
pubmed: 16488880
Nat Methods. 2006 Dec;3(12):995-1000
pubmed: 17072308
Mol Cancer Res. 2012 Dec;10(12):1526-31
pubmed: 23038813
J Clin Invest. 2014 Apr;124(4):1446-53
pubmed: 24691479
Nat Rev Mol Cell Biol. 2016 Jun;17(6):364-78
pubmed: 27165790
Oncotarget. 2016 Aug 2;7(31):50195-50214
pubmed: 27384990
Nat Commun. 2013;4:2848
pubmed: 24270157
Sci Signal. 2014 Sep 02;7(341):re5
pubmed: 25185158
Elife. 2015 Jul 28;4:
pubmed: 26218225
Oncotarget. 2018 Feb 7;9(17):13666-13681
pubmed: 29568385
Biol Cell. 2012 May;104(5):287-96
pubmed: 22283414
Nucleic Acids Res. 2002 May 15;30(10):e47
pubmed: 12000852
Cancer Cell. 2004 Jul;6(1):17-32
pubmed: 15261139
Nucleic Acids Res. 2009 Feb;37(3):e21
pubmed: 19129229
Genes Dev. 2016 May 1;30(9):1002-19
pubmed: 27151975
Science. 2015 May 22;348(6237):880-6
pubmed: 25999502
Cell. 2012 Jun 8;149(6):1207-20
pubmed: 22682244
EMBO J. 2007 Nov 14;26(22):4709-19
pubmed: 17948054
Nature. 2001 Aug 9;412(6847):607-14
pubmed: 11493912
J Biol Chem. 2017 Jun 23;292(25):10549-10563
pubmed: 28487372
Cell Rep. 2013 Oct 17;5(1):194-206
pubmed: 24095731
Nat Chem Biol. 2014 Jul;10(7):542-51
pubmed: 24937072
Nat Commun. 2018 Jul 19;9(1):2834
pubmed: 30026603
Genes Dev. 2005 Sep 15;19(18):2100-10
pubmed: 16166375
Structure. 2012 Feb 8;20(2):340-9
pubmed: 22325781
Nucleic Acids Res. 2014;42(16):10550-63
pubmed: 25114055
Biochem J. 2015 Jun 1;468(2):227-44
pubmed: 25774876
EMBO Rep. 2007 Jan;8(1):56-62
pubmed: 17159921
Cell Rep. 2017 Sep 5;20(10):2468-2479
pubmed: 28877478
EMBO J. 2011 Aug 09;30(19):4047-58
pubmed: 21829167
Oncol Lett. 2017 Jan;13(1):3-12
pubmed: 28123515
J Clin Invest. 2014 May;124(5):2260-76
pubmed: 24743148
Nat Rev Cancer. 2016 Aug 23;16(9):582-98
pubmed: 27550820
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19848-53
pubmed: 17167050
Nucleic Acids Res. 1994 Aug 11;22(15):2938-44
pubmed: 8065905
Cell Cycle. 2016 Jul 2;15(13):1767-78
pubmed: 27163456
Ageing Res Rev. 2002 Sep;1(4):705-20
pubmed: 12208239
Science. 2007 Nov 2;318(5851):798-801
pubmed: 17916692
Nucleic Acids Res. 2001 Mar 15;29(6):1373-80
pubmed: 11239004
Nat Commun. 2010 Oct 19;1:100
pubmed: 20981028
Mol Cells. 2018 Sep 30;41(9):842-852
pubmed: 30157580
J Exp Med. 2017 Aug 7;214(8):2349-2368
pubmed: 28684431
Nat Cell Biol. 2015 Sep;17(9):1193-204
pubmed: 26302407
EMBO J. 2017 Nov 2;36(21):3232-3249
pubmed: 29030483
Nat Commun. 2018 Jul 19;9(1):2827
pubmed: 30026550