Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage.
BRCA1 Protein
/ genetics
Cell Line, Tumor
DNA Breaks, Single-Stranded
/ drug effects
DNA Damage
/ drug effects
DNA Glycosylases
/ antagonists & inhibitors
Drug Resistance, Neoplasm
/ genetics
Female
Homologous Recombination
/ drug effects
Humans
Ovarian Neoplasms
/ drug therapy
Oxidation-Reduction
/ drug effects
Phthalazines
/ adverse effects
Piperazines
/ adverse effects
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
/ genetics
Reactive Oxygen Species
/ metabolism
Synthetic Lethal Mutations
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
26 09 2019
26 09 2019
Historique:
accepted:
12
07
2019
revised:
11
06
2019
received:
01
03
2019
pubmed:
23
7
2019
medline:
18
12
2019
entrez:
23
7
2019
Statut:
ppublish
Résumé
Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.
Identifiants
pubmed: 31329989
pii: 5536981
doi: 10.1093/nar/gkz624
pmc: PMC6753488
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Reactive Oxygen Species
0
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
DNA Glycosylases
EC 3.2.2.-
mutY adenine glycosylase
EC 3.2.2.-
oxoguanine glycosylase 1, human
EC 3.2.2.-
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9132-9143Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
J Bacteriol. 1992 Oct;174(20):6321-5
pubmed: 1328155
Nucleic Acids Res. 2015 Apr 30;43(8):4028-38
pubmed: 25813046
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6
pubmed: 24085845
Nat Rev Genet. 2008 Aug;9(8):619-31
pubmed: 18626472
PLoS Genet. 2014 Apr 03;10(4):e1004256
pubmed: 24698998
Nature. 1991 Jan 31;349(6308):431-4
pubmed: 1992344
J Biol Chem. 2015 Apr 17;290(16):9986-99
pubmed: 25694431
Front Biosci (Landmark Ed). 2017 Mar 1;22:1493-1522
pubmed: 28199214
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5593-8
pubmed: 19307563
DNA Repair (Amst). 2003 Sep 18;2(9):955-69
pubmed: 12967653
Cancers (Basel). 2018 Dec 04;10(12):
pubmed: 30518089
Oncotarget. 2015 Oct 6;6(30):29456-68
pubmed: 26336131
Cancer Res. 2012 Nov 1;72(21):5588-99
pubmed: 23118055
Mol Cancer Ther. 2014 Feb;13(2):433-43
pubmed: 24356813
Biochem Soc Trans. 2006 Nov;34(Pt 5):633-45
pubmed: 17052168
N Engl J Med. 2003 Feb 27;348(9):791-9
pubmed: 12606733
Nucleic Acids Res. 2011 Apr;39(8):3166-75
pubmed: 21183466
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Nature. 2018 Jul;559(7713):285-289
pubmed: 29973717
Sci Rep. 2014 Apr 15;4:4689
pubmed: 24732879
Mol Cell Biol. 2007 Aug;27(15):5597-605
pubmed: 17548475
Transl Oncol. 2014 May 13;:
pubmed: 24836647
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
J Biol Chem. 2011 Dec 30;286(52):44679-90
pubmed: 22057269
DNA Repair (Amst). 2010 May 4;9(5):542-50
pubmed: 20197241
EMBO J. 1997 Oct 15;16(20):6314-22
pubmed: 9321410
DNA Repair (Amst). 2007 Jun 1;6(6):695-711
pubmed: 17337257
Mutat Res. 2017 Jan - Mar;771:99-127
pubmed: 28342455
Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18201-6
pubmed: 19820168
Cancer Metastasis Rev. 1994 Jun;13(2):139-68
pubmed: 7923547
Exp Cell Res. 2014 Nov 15;329(1):2-8
pubmed: 25176342
Nucleic Acids Res. 2017 Mar 17;45(5):2546-2557
pubmed: 27965414
Science. 2018 Nov 16;362(6416):834-839
pubmed: 30442810
Genome Med. 2018 Dec 28;10(1):101
pubmed: 30593284
Mutat Res. 2003 Oct 29;531(1-2):127-39
pubmed: 14637250
Nature. 2007 May 31;447(7144):606-8
pubmed: 17507928
Mol Cancer Ther. 2013 Nov;12(11):2591-600
pubmed: 23966622
J Bacteriol. 1999 Oct;181(19):6210-3
pubmed: 10498741
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8010-5
pubmed: 9223305
Nature. 2008 Feb 28;451(7182):1111-5
pubmed: 18264088
Nat Commun. 2018 May 10;9(1):1849
pubmed: 29748565
Recent Results Cancer Res. 2018;211:217-233
pubmed: 30069770
Int J Mol Sci. 2017 Oct 08;18(10):
pubmed: 28991194
Mutat Res. 2002 Dec 29;510(1-2):81-90
pubmed: 12459445
Cell. 2012 May 25;149(5):1008-22
pubmed: 22579044
Nat Rev Cancer. 2011 Dec 23;12(1):68-78
pubmed: 22193408
Methods Mol Biol. 2018;1703:21-45
pubmed: 29177731
Nature. 2008 Feb 28;451(7182):1116-20
pubmed: 18264087
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3406-11
pubmed: 21300883
Nucleic Acids Res. 1998 Nov 15;26(22):5123-33
pubmed: 9801309