Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient restriction.
DNA base damage
DNA base-excision repair
DNA damage response
DNA double-strand breaks
DNA repair
DNA single-strand breaks
Integrated stress response
Tumour microenvironment
Tumour stroma
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
30 03 2020
30 03 2020
Historique:
received:
02
12
2019
accepted:
16
03
2020
entrez:
2
4
2020
pubmed:
2
4
2020
medline:
30
9
2020
Statut:
epublish
Résumé
Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Hence, tight adaptation of BER capacity is essential for DNA stability. However, counterintuitive to this, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Based on our previous findings that XRCC1 downregulation causes wide-ranging anabolic changes, we hypothesised that BER depletion could enhance cellular survival under stress, such as nutrient restriction. Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. Furthermore, we demonstrate that SSBs, induced either through depletion of the transcription factor Sp1, responsible for XRCC1 levels, or through prolonged oxidative stress, trigger ISR-mediated cell survival under nutrient restriction as well. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks. Our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.
Sections du résumé
BACKGROUND
Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Hence, tight adaptation of BER capacity is essential for DNA stability. However, counterintuitive to this, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Based on our previous findings that XRCC1 downregulation causes wide-ranging anabolic changes, we hypothesised that BER depletion could enhance cellular survival under stress, such as nutrient restriction.
RESULTS
Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. Furthermore, we demonstrate that SSBs, induced either through depletion of the transcription factor Sp1, responsible for XRCC1 levels, or through prolonged oxidative stress, trigger ISR-mediated cell survival under nutrient restriction as well. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks.
CONCLUSIONS
Our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.
Identifiants
pubmed: 32228693
doi: 10.1186/s12915-020-00771-x
pii: 10.1186/s12915-020-00771-x
pmc: PMC7106853
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
36Références
Clin Cancer Res. 2005 Sep 1;11(17):6205-11
pubmed: 16144922
Redox Biol. 2014 Jan 09;2:457-65
pubmed: 24624335
Oncotarget. 2018 Feb 7;9(17):13666-13681
pubmed: 29568385
Nat Neurosci. 2009 Aug;12(8):973-80
pubmed: 19633665
J Cell Sci. 2013 Mar 15;126(Pt 6):1488-97
pubmed: 23378024
Clin Cancer Res. 2013 Nov 1;19(21):5879-89
pubmed: 23995859
PLoS One. 2012;7(6):e39956
pubmed: 22768182
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21105-10
pubmed: 22160723
DNA Repair (Amst). 2019 Sep;81:102664
pubmed: 31324530
Nucleic Acids Res. 2013 Apr 1;41(6):3483-90
pubmed: 23408852
Nucleic Acids Res. 2014 Feb;42(4):2320-9
pubmed: 24293653
Int J Radiat Biol. 1999 May;75(5):553-61
pubmed: 10374937
Clin Cancer Res. 2012 May 15;18(10):2987-96
pubmed: 22452940
DNA Repair (Amst). 2010 Jun 4;9(6):604-16
pubmed: 20399712
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):3997-4002
pubmed: 25775545
Semin Cancer Biol. 2014 Apr;25:23-32
pubmed: 24406211
Mech Ageing Dev. 2014 Jun;138:26-44
pubmed: 24686308
Med Oncol. 2012 Dec;29(5):3620-5
pubmed: 22798271
Expert Opin Ther Targets. 2012 Dec;16(12):1189-202
pubmed: 23009153
EMBO J. 2009 Oct 21;28(20):3207-15
pubmed: 19713937
EMBO Rep. 2016 Oct;17(10):1374-1395
pubmed: 27629041
Nucleic Acids Res. 2018 Feb 28;46(4):1834-1846
pubmed: 29294106
Mol Cell. 2003 Mar;11(3):619-33
pubmed: 12667446
Cancer Cell. 2012 Mar 20;21(3):309-22
pubmed: 22439926
Nucleic Acids Res. 2005 May 02;33(8):2512-20
pubmed: 15867196
Int J Mol Sci. 2016 Jun 01;17(6):
pubmed: 27258260
Nature. 2005 Apr 14;434(7035):864-70
pubmed: 15829956
Mutat Res. 2002 Jun 27;518(1):9-20
pubmed: 12063063
Tumour Biol. 2012 Feb;33(1):111-9
pubmed: 22081374
Mol Cell. 2017 Dec 7;68(5):885-900.e6
pubmed: 29220654
Nat Rev Cancer. 2016 Jan;16(1):20-33
pubmed: 26678314
Nat Commun. 2018 Aug 17;9(1):3292
pubmed: 30120226
Nucleic Acids Res. 2016 Apr 20;44(7):3165-75
pubmed: 26773055
Nature. 2009 Oct 22;461(7267):1071-8
pubmed: 19847258
Cancer Res. 1995 Jun 1;55(11):2284-92
pubmed: 7757977
Cold Spring Harb Perspect Med. 2015 Sep 18;5(10):
pubmed: 26385091
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210
pubmed: 23486281
J Innate Immun. 2019;11(1):74-85
pubmed: 30296787
Mol Cancer Res. 2014 Oct;12(10):1407-15
pubmed: 25030372
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12285-E12294
pubmed: 30538199
Nat Rev Mol Cell Biol. 2017 Oct;18(10):610-621
pubmed: 28676700
Mol Cell Biochem. 2013 May;377(1-2):45-53
pubmed: 23435956
DNA Repair (Amst). 2014 Jul;19:14-26
pubmed: 24780558
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17010-5
pubmed: 17940040
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Trends Cell Biol. 2017 Nov;27(11):863-875
pubmed: 28734735
Mol Cell. 2008 Feb 29;29(4):477-87
pubmed: 18313385
J Med Chem. 2012 Aug 23;55(16):7193-207
pubmed: 22827572
DNA Repair (Amst). 2017 Nov;59:82-105
pubmed: 28963982
Nucleic Acids Res. 2015 Apr 20;43(7):3667-79
pubmed: 25800737
Cancer Res. 2007 Jan 1;67(1):26-31
pubmed: 17210680
Nucleic Acids Res. 2011 Oct;39(18):7992-8004
pubmed: 21737425
Trends Mol Med. 2013 Aug;19(8):447-53
pubmed: 23769623
Trends Endocrinol Metab. 2017 Nov;28(11):794-806
pubmed: 28797581
Cancer Res. 2009 Nov 15;69(22):8629-35
pubmed: 19887610
Nature. 1993 Apr 22;362(6422):709-15
pubmed: 8469282