RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
27 10 2023
27 10 2023
Historique:
accepted:
24
08
2023
revised:
10
08
2023
received:
09
05
2023
medline:
30
10
2023
pubmed:
12
9
2023
entrez:
12
9
2023
Statut:
ppublish
Résumé
Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
Identifiants
pubmed: 37697435
pii: 7269184
doi: 10.1093/nar/gkad733
pmc: PMC10602868
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
DNA-Binding Proteins
0
Exoribonucleases
EC 3.1.-
RNF8 protein, human
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
XRN2 protein, human
EC 3.1.13.1
Brca1 protein, mouse
0
Rnf8 protein, mouse
EC 2.3.2.27
Xrn2 protein, mouse
EC 3.1.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10484-10505Subventions
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
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
J Clin Invest. 2018 Oct 1;128(10):4525-4542
pubmed: 30222135
Genes Dev. 2004 May 15;18(10):1144-53
pubmed: 15131084
Nature. 2015 Nov 19;527(7578):389-93
pubmed: 26503038
Cancer Metastasis Rev. 2013 Jun;32(1-2):25-37
pubmed: 23093327
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Cell. 2017 Aug 10;170(4):787-799.e18
pubmed: 28802046
Trends Genet. 2021 Jun;37(6):566-581
pubmed: 33485674
Cell. 2009 Feb 6;136(3):435-46
pubmed: 19203579
Cell Rep. 2019 Nov 26;29(9):2890-2900.e5
pubmed: 31775053
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Nature. 2020 Sep;585(7824):298-302
pubmed: 32669707
PLoS Genet. 2008 Jun 27;4(6):e1000110
pubmed: 18584027
J Exp Med. 2010 May 10;207(5):983-97
pubmed: 20385750
Cell. 2019 Oct 31;179(4):813-827
pubmed: 31675495
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Methods Enzymol. 2017;591:55-82
pubmed: 28645379
Cell. 2010 Jun 11;141(6):970-81
pubmed: 20550933
Cell Rep. 2018 May 8;23(6):1891-1905
pubmed: 29742442
Cell. 2012 May 25;149(5):979-93
pubmed: 22608084
Cancer Res. 2020 Nov 1;80(21):4601-4609
pubmed: 32747362
Genes Dev. 2014 Jul 1;28(13):1384-96
pubmed: 24990962
Cell. 2019 Oct 17;179(3):604-618
pubmed: 31607512
Mol Cell. 2011 Jun 24;42(6):794-805
pubmed: 21700224
Mol Cell. 2017 May 18;66(4):458-472.e5
pubmed: 28525740
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
JAMA. 2017 Jun 20;317(23):2402-2416
pubmed: 28632866
Life Sci Alliance. 2020 Aug 3;3(10):
pubmed: 32747416
J Cell Biol. 2021 Sep 6;220(9):
pubmed: 34232287
Nat Rev Cancer. 2015 May;15(5):276-89
pubmed: 25907220
Nat Rev Clin Oncol. 2018 Sep;15(9):564-576
pubmed: 29955114
PLoS Genet. 2016 Jul 20;12(7):e1006107
pubmed: 27437695
Mol Cell. 2012 May 11;46(3):311-24
pubmed: 22483619
Nature. 2023 Jan;613(7942):187-194
pubmed: 36544021
Mol Cell. 2015 Feb 19;57(4):636-647
pubmed: 25699710
Nucleic Acids Res. 2018 Nov 16;46(20):11002-11013
pubmed: 30169671
Annu Rev Cancer Biol. 2018 Mar;2:313-336
pubmed: 30345412
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Cancer Cell. 2012 Jul 10;22(1):106-16
pubmed: 22789542
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
DNA Repair (Amst). 2018 Nov;71:69-81
pubmed: 30190235
Genes Dev. 2011 Oct 1;25(19):2041-56
pubmed: 21979917
J Clin Invest. 2021 Feb 1;131(3):
pubmed: 33529165
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Cancer Res. 2006 Jan 1;66(1):41-5
pubmed: 16397213
Neoplasia. 2009 Jul;11(7):683-91
pubmed: 19568413
Nat Commun. 2020 Aug 7;11(1):3940
pubmed: 32769985
Oncogene. 2021 Apr;40(17):3001-3014
pubmed: 33716297
Genes Dev. 2014 Sep 1;28(17):1957-75
pubmed: 25184681
Mol Cell. 2022 Jun 16;82(12):2267-2297
pubmed: 35508167
Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18
pubmed: 24326623
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Nat Rev Mol Cell Biol. 2020 May;21(5):284-299
pubmed: 32094664
Nat Struct Mol Biol. 2010 Jun;17(6):688-95
pubmed: 20453858
Nucleic Acids Res. 2023 Apr 11;51(6):2818-2837
pubmed: 36864660
Genome Biol. 2016 Feb 22;17:31
pubmed: 26899170
Cell. 2017 Aug 10;170(4):774-786.e19
pubmed: 28802045
Nat Rev Mol Cell Biol. 2016 May 23;17(6):379-94
pubmed: 27211488
Genome Res. 2018 Sep;28(9):1405-1414
pubmed: 30108179
Nucleic Acids Res. 2020 Jun 19;48(11):6032-6052
pubmed: 32427332
Mol Cell. 2017 Oct 19;68(2):414-430.e8
pubmed: 29053959
Cell. 2010 Apr 16;141(2):243-54
pubmed: 20362325