Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns.
ataxia-telangiectasia
cell senescence
oxygen concentration
transcriptome
Journal
Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
23
04
2023
received:
28
11
2022
accepted:
28
04
2023
medline:
10
8
2023
pubmed:
31
5
2023
entrez:
31
5
2023
Statut:
ppublish
Résumé
The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA-seq analysis of A-T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A-T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A-T cells. We observed in them a robust activation of interferon-stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non-canonical cGAS-STING-mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A-T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence-associated secretory phenotype (SASP) factors known for their paracrine pro-fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients and its associated symptoms, which develop as the patients advance in age.
Identifiants
pubmed: 37254625
doi: 10.1111/acel.13869
pmc: PMC10410012
doi:
Substances chimiques
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13869Informations de copyright
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Références
Nat Cell Biol. 2003 Aug;5(8):741-7
pubmed: 12855956
Annu Rev Pathol. 2010;5:99-118
pubmed: 20078217
Hum Mol Genet. 1996 Apr;5(4):433-9
pubmed: 8845835
Nature. 2018 Jan 25;553(7689):467-472
pubmed: 29342134
Genes (Basel). 2021 Aug 31;12(9):
pubmed: 34573351
Aging Cell. 2021 Sep;20(9):e13468
pubmed: 34459078
Nat Commun. 2019 May 21;10(1):2261
pubmed: 31113940
Nat Genet. 1996 Jul;13(3):350-3
pubmed: 8673136
Ageing Res Rev. 2022 Aug;79:101653
pubmed: 35644374
Nat Rev Mol Cell Biol. 2021 Dec;22(12):796-814
pubmed: 34429537
Lancet. 1975 Nov 22;2(7943):1048
pubmed: 53540
Am J Reprod Immunol. 2018 Jun;79(6):e12826
pubmed: 29446169
Antioxid Redox Signal. 2021 Feb 1;34(4):324-334
pubmed: 32212823
Nucleic Acids Res. 2014 Feb;42(3):e21
pubmed: 24366880
Science. 2021 Oct 29;374(6567):eabb3420
pubmed: 34709885
Cell. 2019 Jan 24;176(3):505-519.e22
pubmed: 30612738
Trends Cell Biol. 2018 Jun;28(6):436-453
pubmed: 29477613
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4337-41
pubmed: 7753808
Keio J Med. 1998 Sep;47(3):174-82
pubmed: 9785764
Science. 2010 Oct 22;330(6003):517-21
pubmed: 20966255
J Gerontol A Biol Sci Med Sci. 2022 Nov 21;77(11):2207-2218
pubmed: 35524726
J Proteome Res. 2019 Feb 1;18(2):623-632
pubmed: 30450911
Orphanet J Rare Dis. 2016 Nov 25;11(1):159
pubmed: 27884168
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Genome Biol. 2014;15(12):550
pubmed: 25516281
Bioinformatics. 2011 Jun 15;27(12):1739-40
pubmed: 21546393
Curr Biol. 2017 Sep 11;27(17):2652-2660.e4
pubmed: 28844647
Cell. 2017 Feb 9;168(4):644-656
pubmed: 28187286
Physiol Rev. 2019 Jan 1;99(1):161-234
pubmed: 30354965
Nature. 2003 Jan 30;421(6922):499-506
pubmed: 12556884
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
J Cell Physiol. 1976 Nov;89(3):429-31
pubmed: 977661
Nat Rev Dis Primers. 2019 Sep 19;5(1):64
pubmed: 31537806
FEBS J. 2020 Jul;287(13):2636-2646
pubmed: 32145148
Nucleic Acids Res. 2016 Jul 8;44(W1):W147-53
pubmed: 27190236
Nature. 2017 Aug 24;548(7668):466-470
pubmed: 28759889
Gigascience. 2021 Feb 16;10(2):
pubmed: 33590861
Science. 1995 Jun 23;268(5218):1749-53
pubmed: 7792600
Int J Mol Sci. 2021 Dec 06;22(23):
pubmed: 34884978
Mol Cell. 2021 May 6;81(9):2041-2052.e6
pubmed: 33823141
Nat Metab. 2021 Oct;3(10):1290-1301
pubmed: 34663974
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Genes Dev. 2020 Dec 1;34(23-24):1565-1576
pubmed: 33262144
Cell Syst. 2018 Apr 25;6(4):484-495.e5
pubmed: 29605183
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Life Sci Alliance. 2021 Jan 14;4(3):
pubmed: 33446491
Front Pharmacol. 2021 Sep 07;12:737570
pubmed: 34557100
Nucleic Acids Res. 2019 May 7;47(8):e47
pubmed: 30783653
Stem Cells Transl Med. 2012 Jul;1(7):523-35
pubmed: 23197857
Cancer Res. 2020 Dec 1;80(23):5245-5256
pubmed: 33115807
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
FEBS J. 2023 Mar;290(5):1212-1220
pubmed: 34921507
Genome Res. 2012 Sep;22(9):1760-74
pubmed: 22955987
Bioinformatics. 2007 Jul 15;23(14):1846-7
pubmed: 17496320
Annu Rev Biochem. 2022 Jun 21;91:599-628
pubmed: 35287475
Bioinformatics. 2003 Sep 22;19(14):1787-99
pubmed: 14512350
Trends Genet. 2022 Jun;38(6):598-612
pubmed: 35346511
Cancers (Basel). 2021 Sep 11;13(18):
pubmed: 34572787
Aging Cell. 2020 Oct;19(10):e13234
pubmed: 32918364
Cytokine. 2019 May;117:15-22
pubmed: 30776684
J Mol Biol. 2019 Jun 14;431(13):2398-2406
pubmed: 31100387
Ageing Res Rev. 2017 Jan;33:76-88
pubmed: 27181190
PLoS One. 2009 May 22;4(5):e5666
pubmed: 19461895
Clin Sci (Lond). 2020 Oct 30;134(20):2681-2706
pubmed: 33084883
Biogerontology. 2009 Jun;10(3):253-66
pubmed: 18830681
Radiat Res. 2001 Nov;156(5 Pt 2):642-7
pubmed: 11604086
Nucleic Acids Res. 2016 Jan 4;44(D1):D717-25
pubmed: 26590259
Nat Commun. 2023 Feb 2;14(1):556
pubmed: 36732527
Annu Rev Med. 2015;66:129-43
pubmed: 25423595
BMC Bioinformatics. 2003 Jan 13;4:2
pubmed: 12525261
Exp Cell Res. 1982 Jul;140(1):191-9
pubmed: 6213420
Environ Mol Mutagen. 2017 Jun;58(5):235-263
pubmed: 28485537
Nature. 2018 Jul;559(7713):269-273
pubmed: 29973723
Nat Rev Drug Discov. 2007 Dec;6(12):975-90
pubmed: 18049472
Aging Cell. 2023 Aug;22(8):e13869
pubmed: 37254625
Cell Rep. 2018 Feb 20;22(8):2006-2015
pubmed: 29466729
Nat Rev Mol Cell Biol. 2021 Feb;22(2):75-95
pubmed: 33328614
Elife. 2021 Jan 29;10:
pubmed: 33512317
Nature. 2017 Oct 19;550(7676):402-406
pubmed: 28976970