Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient restriction.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190720 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7007 (Electronic) Linking ISSN: 17417007 NLM ISO Abbreviation: BMC Biol Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

DNA Damage* ; DNA Repair*; Nutrients/*deficiency; Cell Line ; Cell Survival ; Fibroblasts ; Humans

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.

Clin Cancer Res. 2005 Sep 1;11(17):6205-11. (PMID: 16144922)
Redox Biol. 2014 Jan 09;2:457-65. (PMID: 24624335)
Oncotarget. 2018 Feb 7;9(17):13666-13681. (PMID: 29568385)
Nat Neurosci. 2009 Aug;12(8):973-80. (PMID: 19633665)
J Cell Sci. 2013 Mar 15;126(Pt 6):1488-97. (PMID: 23378024)
Clin Cancer Res. 2013 Nov 1;19(21):5879-89. (PMID: 23995859)
Cold Spring Harb Perspect Med. 2015 Sep 18;5(10):. (PMID: 26385091)
PLoS One. 2012;7(6):e39956. (PMID: 22768182)
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21105-10. (PMID: 22160723)
DNA Repair (Amst). 2019 Sep;81:102664. (PMID: 31324530)
Nucleic Acids Res. 2013 Apr 1;41(6):3483-90. (PMID: 23408852)
Nucleic Acids Res. 2014 Feb;42(4):2320-9. (PMID: 24293653)
Int J Radiat Biol. 1999 May;75(5):553-61. (PMID: 10374937)
Clin Cancer Res. 2012 May 15;18(10):2987-96. (PMID: 22452940)
DNA Repair (Amst). 2010 Jun 4;9(6):604-16. (PMID: 20399712)
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):3997-4002. (PMID: 25775545)
Semin Cancer Biol. 2014 Apr;25:23-32. (PMID: 24406211)
Mech Ageing Dev. 2014 Jun;138:26-44. (PMID: 24686308)
Med Oncol. 2012 Dec;29(5):3620-5. (PMID: 22798271)
Expert Opin Ther Targets. 2012 Dec;16(12):1189-202. (PMID: 23009153)
EMBO J. 2009 Oct 21;28(20):3207-15. (PMID: 19713937)
EMBO Rep. 2016 Oct;17(10):1374-1395. (PMID: 27629041)
Nucleic Acids Res. 2018 Feb 28;46(4):1834-1846. (PMID: 29294106)
Mol Cell. 2003 Mar;11(3):619-33. (PMID: 12667446)
Cancer Cell. 2012 Mar 20;21(3):309-22. (PMID: 22439926)
Nucleic Acids Res. 2005 May 02;33(8):2512-20. (PMID: 15867196)
Int J Mol Sci. 2016 Jun 01;17(6):. (PMID: 27258260)
Nature. 2005 Apr 14;434(7035):864-70. (PMID: 15829956)
Mutat Res. 2002 Jun 27;518(1):9-20. (PMID: 12063063)
Tumour Biol. 2012 Feb;33(1):111-9. (PMID: 22081374)
Mol Cell. 2017 Dec 7;68(5):885-900.e6. (PMID: 29220654)
Nat Rev Cancer. 2016 Jan;16(1):20-33. (PMID: 26678314)
Nat Commun. 2018 Aug 17;9(1):3292. (PMID: 30120226)
Nucleic Acids Res. 2016 Apr 20;44(7):3165-75. (PMID: 26773055)
Nature. 2009 Oct 22;461(7267):1071-8. (PMID: 19847258)
Cancer Res. 1995 Jun 1;55(11):2284-92. (PMID: 7757977)
J Innate Immun. 2019;11(1):74-85. (PMID: 30296787)
Mol Cancer Res. 2014 Oct;12(10):1407-15. (PMID: 25030372)
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12285-E12294. (PMID: 30538199)
Nat Rev Mol Cell Biol. 2017 Oct;18(10):610-621. (PMID: 28676700)
Mol Cell Biochem. 2013 May;377(1-2):45-53. (PMID: 23435956)
DNA Repair (Amst). 2014 Jul;19:14-26. (PMID: 24780558)
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17010-5. (PMID: 17940040)
Nature. 2013 Aug 22;500(7463):415-21. (PMID: 23945592)
Trends Cell Biol. 2017 Nov;27(11):863-875. (PMID: 28734735)
Mol Cell. 2008 Feb 29;29(4):477-87. (PMID: 18313385)
J Med Chem. 2012 Aug 23;55(16):7193-207. (PMID: 22827572)
DNA Repair (Amst). 2017 Nov;59:82-105. (PMID: 28963982)
Nucleic Acids Res. 2015 Apr 20;43(7):3667-79. (PMID: 25800737)
Cancer Res. 2007 Jan 1;67(1):26-31. (PMID: 17210680)
Nucleic Acids Res. 2011 Oct;39(18):7992-8004. (PMID: 21737425)
Trends Mol Med. 2013 Aug;19(8):447-53. (PMID: 23769623)
Trends Endocrinol Metab. 2017 Nov;28(11):794-806. (PMID: 28797581)
Cancer Res. 2009 Nov 15;69(22):8629-35. (PMID: 19887610)
Nature. 1993 Apr 22;362(6422):709-15. (PMID: 8469282)

Keywords: 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

Date Created: 20200402 Date Completed: 20200929 Latest Revision: 20240727

20250114

PMC7106853

10.1186/s12915-020-00771-x

32228693