Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
22 05 2023
22 05 2023
Historique:
accepted:
14
03
2023
revised:
17
02
2023
received:
31
05
2022
medline:
23
5
2023
pubmed:
18
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.
Identifiants
pubmed: 36928661
pii: 7079642
doi: 10.1093/nar/gkad172
pmc: PMC10201440
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
PAF1 protein, human
0
RNA Polymerase II
EC 2.7.7.-
MePCE protein, human
EC 2.1.1.-
Methyltransferases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4341-4362Subventions
Organisme : Cancer Research UK
ID : C17183/A23303
Pays : United Kingdom
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Cancer Res. 2016 May 1;76(9):2778-90
pubmed: 27197267
J Biol Chem. 2013 Jul 19;288(29):21173-21183
pubmed: 23744076
Blood. 2021 Apr 22;137(16):2171-2181
pubmed: 33270841
Oncogene. 2021 Apr;40(17):3001-3014
pubmed: 33716297
Nat Commun. 2017 Jun 26;8:15908
pubmed: 28649985
Mutat Res Genet Toxicol Environ Mutagen. 2022 Apr-May;876-877:503450
pubmed: 35483781
Cancer Genet. 2015 May;208(5):237-40
pubmed: 25800897
Cell Rep. 2018 Jan 23;22(4):1031-1039
pubmed: 29386125
Genes Dev. 2014 Jul 1;28(13):1384-96
pubmed: 24990962
Nat Chem Biol. 2019 Feb;15(2):132-140
pubmed: 30559425
J Biol Chem. 2001 Aug 24;276(34):31793-9
pubmed: 11431468
JAMA. 2017 Jun 20;317(23):2402-2416
pubmed: 28632866
DNA Repair (Amst). 2014 Jul;19:84-94
pubmed: 24746923
Mol Cell. 2007 Jul 20;27(2):262-274
pubmed: 17643375
Cell Rep. 2016 Jun 14;15(11):2488-99
pubmed: 27264184
Transcription. 2019 Apr;10(2):57-75
pubmed: 30227759
J Cell Biol. 2021 Sep 6;220(9):
pubmed: 34232287
CA Cancer J Clin. 2019 Jan;69(1):7-34
pubmed: 30620402
Trends Genet. 2019 Oct;35(10):724-733
pubmed: 31358304
Nucleic Acids Res. 2010 Jan;38(2):360-9
pubmed: 19906723
Molecules. 2019 Oct 27;24(21):
pubmed: 31717862
Aging Cell. 2006 Apr;5(2):187-95
pubmed: 16626397
Annu Rev Genet. 2013;47:483-508
pubmed: 24050178
Nat Rev Mol Cell Biol. 2017 Apr;18(4):263-273
pubmed: 28248323
Genes Dev. 2003 Jun 1;17(11):1402-14
pubmed: 12782658
Cancers (Basel). 2021 Dec 27;14(1):
pubmed: 35008272
Mol Cell. 2012 Apr 27;46(2):115-24
pubmed: 22541554
Prz Menopauzalny. 2016 Dec;15(4):215-219
pubmed: 28250726
Nature. 2015 Feb 12;518(7538):258-62
pubmed: 25642963
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7798-803
pubmed: 19416841
Mol Cell. 2015 Feb 19;57(4):636-647
pubmed: 25699710
Nature. 2001 Nov 15;414(6861):322-5
pubmed: 11713533
J Breast Cancer. 2019 Jan 22;22(1):1-14
pubmed: 30941229
Clin Epigenetics. 2019 May 16;11(1):81
pubmed: 31097014
Cell Rep. 2018 Feb 6;22(6):1374-1383
pubmed: 29425494
Trends Biotechnol. 2019 Jan;37(1):38-55
pubmed: 30177380
Br J Pharmacol. 2014 Jan;171(1):55-68
pubmed: 24102143
Genes Dev. 2011 Oct 1;25(19):2041-56
pubmed: 21979917
Cell. 2015 Aug 27;162(5):1003-15
pubmed: 26279188
J Clin Invest. 2021 Feb 1;131(3):
pubmed: 33529165
Nat Struct Mol Biol. 2017 May 4;24(5):439-443
pubmed: 28471430
Nature. 2001 Nov 15;414(6861):317-22
pubmed: 11713532
Trends Cell Biol. 2019 Oct;29(10):820-834
pubmed: 31421928
Transcription. 2011 May;2(3):103-108
pubmed: 21922053
N Engl J Med. 2020 May 28;382(22):2091-2102
pubmed: 32343890
Nat Struct Mol Biol. 2014 Apr;21(4):366-74
pubmed: 24658350
Mol Cell. 2003 Oct;12(4):971-82
pubmed: 14580347
Transcription. 2018;9(2):95-101
pubmed: 28820318
Interdiscip Top Gerontol. 2014;39:45-61
pubmed: 24862014
Nat Cell Biol. 2014 Jan;16(1):2-9
pubmed: 24366029
Cancer. 2015 Jan 15;121(2):269-75
pubmed: 25224030
Nature. 2020 Sep;585(7824):298-302
pubmed: 32669707