Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade.
BRCA2
MRE11
synthetic lethality
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
30 Jun 2023
30 Jun 2023
Historique:
received:
10
05
2023
revised:
22
06
2023
accepted:
23
06
2023
medline:
17
7
2023
pubmed:
14
7
2023
entrez:
14
7
2023
Statut:
epublish
Résumé
The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40
Identifiants
pubmed: 37446144
pii: ijms241310966
doi: 10.3390/ijms241310966
pmc: PMC10341502
pii:
doi:
Substances chimiques
6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone
0
DNA-Binding Proteins
0
MRE11 Homologue Protein
EC 3.1.-
BRCA2 Protein
0
BRCA2 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Naaz-Coker Ovarian Cancer Fellowship, University of Nottingham
ID : 01
Références
Nat Commun. 2017 Oct 16;8(1):859
pubmed: 29038466
Annu Rev Biochem. 2018 Jun 20;87:263-294
pubmed: 29709199
J Chem Inf Model. 2021 Aug 23;61(8):3891-3898
pubmed: 34278794
Nucleic Acids Res. 2020 Dec 16;48(22):12778-12791
pubmed: 33275133
DNA Repair (Amst). 2011 Oct 10;10(10):1060-5
pubmed: 21900052
Environ Mol Mutagen. 2011 Mar;52(2):153-60
pubmed: 20839229
Oncogene. 2008 Jan 24;27(5):565-73
pubmed: 17891185
Nat Commun. 2017 Oct 16;8(1):860
pubmed: 29038425
Cell. 2011 May 13;145(4):529-42
pubmed: 21565612
Trends Cell Biol. 2019 Oct;29(10):820-834
pubmed: 31421928
Mol Oncol. 2020 Jun;14(6):1121-1123
pubmed: 32255263
Cancer Res. 2012 Jun 1;72(11):2814-21
pubmed: 22447567
N Engl J Med. 2016 Sep 22;375(12):1109-12
pubmed: 27653561
Sci Adv. 2020 May 29;6(22):eaaz4126
pubmed: 32523988
Science. 2017 Mar 17;355(6330):1152-1158
pubmed: 28302823
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Nat Chem Biol. 2008 Feb;4(2):119-25
pubmed: 18176557
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
Int J Biochem Cell Biol. 2019 Feb;107:128-139
pubmed: 30590106
Mol Cell Biol. 1999 Jan;19(1):556-66
pubmed: 9858579
Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205
pubmed: 31114916
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):686-91
pubmed: 21148102
Cell Cycle. 2005 Jun;4(6):737-40
pubmed: 15908798
Biochim Biophys Acta Rev Cancer. 2021 Dec;1876(2):188633
pubmed: 34619333
Mol Cancer. 2019 Nov 26;18(1):169
pubmed: 31767017
Genes (Basel). 2021 Aug 10;12(8):
pubmed: 34440403
Cancers (Basel). 2020 Jun 17;12(6):
pubmed: 32560564
Nature. 2011 Oct 16;479(7372):241-4
pubmed: 22002605
Nucleic Acids Res. 2016 May 19;44(9):4189-99
pubmed: 26873923
EBioMedicine. 2020 Nov;61:103046
pubmed: 33038760
Genet Med. 2010 May;12(5):245-59
pubmed: 20216074
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Endocr Relat Cancer. 2016 Oct;23(10):T1-T17
pubmed: 27530658
PLoS One. 2022 Sep 15;17(9):e0273736
pubmed: 36107942
NPJ Precis Oncol. 2022 Jul 19;6(1):51
pubmed: 35853939
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Obstet Gynecol Clin North Am. 2010 Mar;37(1):109-33, Table of Contents
pubmed: 20494261
Mol Cancer Ther. 2021 Nov;20(11):2117-2128
pubmed: 34518297
Exp Cell Res. 2014 Nov 15;329(1):162-9
pubmed: 25447316
Cold Spring Harb Symp Quant Biol. 2017;82:329-338
pubmed: 29686033
Nat Struct Mol Biol. 2011 Jul 06;18(7):748-54
pubmed: 21731065
PLoS One. 2021 Mar 30;16(3):e0248941
pubmed: 33784323
Mol Oncol. 2009 Apr;3(2):138-50
pubmed: 19383375
Structure. 2011 Nov 9;19(11):1591-602
pubmed: 22078559
Mol Cell. 2014 Jan 9;53(1):7-18
pubmed: 24316220
Mol Oncol. 2020 Jun;14(6):1124-1133
pubmed: 32175645