Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens.
BRCA2 Protein
/ genetics
Biomarkers
Clustered Regularly Interspaced Short Palindromic Repeats
DNA Damage
DNA Repair
Gene Knockout Techniques
HeLa Cells
Homologous Recombination
/ drug effects
Humans
Lysine Acetyltransferase 5
/ metabolism
Mad2 Proteins
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ isolation & purification
Poly(ADP-ribose) Polymerases
/ drug effects
Rad51 Recombinase
/ genetics
Tumor Suppressor Proteins
/ genetics
Tumor Suppressor p53-Binding Protein 1
Ubiquitin-Protein Ligases
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 11 2020
30 11 2020
Historique:
received:
18
12
2019
accepted:
30
10
2020
entrez:
1
12
2020
pubmed:
2
12
2020
medline:
22
12
2020
Statut:
epublish
Résumé
Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells.
Identifiants
pubmed: 33257658
doi: 10.1038/s41467-020-19961-w
pii: 10.1038/s41467-020-19961-w
pmc: PMC7704667
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
Biomarkers
0
MAD2L2 protein, human
0
Mad2 Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
TP53BP1 protein, human
0
Tumor Suppressor Proteins
0
Tumor Suppressor p53-Binding Protein 1
0
KAT5 protein, human
EC 2.3.1.48
Lysine Acetyltransferase 5
EC 2.3.1.48
HUWE1 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6118Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM134681
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES026184
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA243301
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222349
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM129066
Pays : United States
Références
Elife. 2017 Nov 06;6:
pubmed: 29106372
Gynecol Oncol. 2017 Dec;147(3):695-704
pubmed: 29037806
Cell. 2018 May 3;173(4):972-988.e23
pubmed: 29656893
Drugs. 2019 Jul;79(11):1231-1239
pubmed: 31267481
Mol Cell Biol. 2015 Dec;35(24):4147-57
pubmed: 26438602
Mol Cell. 2017 Aug 3;67(3):374-386.e5
pubmed: 28735897
Trends Cell Biol. 2016 Jan;26(1):52-64
pubmed: 26437586
Lancet Oncol. 2017 Jan;18(1):75-87
pubmed: 27908594
Mol Cell Biol. 2007 Oct;27(20):7028-40
pubmed: 17709392
Nat Struct Mol Biol. 2010 Jun;17(6):688-95
pubmed: 20453858
Cell. 2005 Nov 4;123(3):409-21
pubmed: 16269333
Nat Cell Biol. 2017 Nov;19(11):1371-1378
pubmed: 29035360
Nature. 2018 Jul;559(7713):279-284
pubmed: 29950726
Nat Struct Mol Biol. 2016 Aug;23(8):714-21
pubmed: 27348077
Nature. 2015 May 28;521(7553):541-544
pubmed: 25799992
PLoS One. 2013 Apr 25;8(4):e61520
pubmed: 23634208
Methods Mol Biol. 2012;920:379-91
pubmed: 22941618
J Cell Biol. 2019 Apr 1;218(4):1096-1107
pubmed: 30670471
Br J Cancer. 2016 Aug 9;115(4):431-41
pubmed: 27415012
Nature. 2016 Jul 20;535(7612):382-7
pubmed: 27443740
Nat Struct Mol Biol. 2013 Mar;20(3):317-25
pubmed: 23377543
Open Biol. 2019 Sep 27;9(9):190156
pubmed: 31506018
Cytometry A. 2012 Oct;81(10):922-8
pubmed: 22893507
Cancer Res. 2012 Nov 1;72(21):5588-99
pubmed: 23118055
EMBO Rep. 2016 Jun;17(6):874-86
pubmed: 27146073
Nat Cell Biol. 2019 Apr;21(4):487-497
pubmed: 30804506
Mol Cell. 2016 May 5;62(3):409-421
pubmed: 27153538
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
Nat Protoc. 2015 Sep;10(9):1297-307
pubmed: 26226461
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Nucleic Acids Res. 2016 Jan 29;44(2):648-56
pubmed: 26446986
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Nature. 2018 Jul;559(7713):285-289
pubmed: 29973717
Nature. 2015 Feb 26;518(7540):495-501
pubmed: 25719666
Cancer Discov. 2013 Jan;3(1):68-81
pubmed: 23103855
Cold Spring Harb Protoc. 2016 Mar 01;2016(3):pdb.prot090811
pubmed: 26933250
Nucleic Acids Res. 2018 Sep 28;46(17):8898-8907
pubmed: 30032296
Nature. 2018 Nov;563(7732):522-526
pubmed: 30464262
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Nat Commun. 2018 Dec 21;9(1):5416
pubmed: 30575746
Genome Biol. 2014;15(12):554
pubmed: 25476604
N Engl J Med. 2012 Apr 12;366(15):1382-92
pubmed: 22452356
Nat Commun. 2018 May 10;9(1):1849
pubmed: 29748565
Cell. 2011 May 13;145(4):529-42
pubmed: 21565612
Genes Dev. 2012 Feb 1;26(3):235-40
pubmed: 22267412
Nature. 2018 Aug;560(7716):117-121
pubmed: 30022168
Genes Dev. 2015 Mar 1;29(5):489-94
pubmed: 25737278
Mol Cell Biol. 2018 Mar 29;38(8):
pubmed: 29378830
J Biol Chem. 2014 May 9;289(19):13627-37
pubmed: 24695737
Lancet Oncol. 2017 Sep;18(9):1274-1284
pubmed: 28754483
Commun Biol. 2019 Sep 9;2:335
pubmed: 31508509
Mol Cell Biol. 2010 Jul;30(14):3582-95
pubmed: 20479123
Mol Cell Biol. 2016 May 02;36(10):1595-607
pubmed: 26976643
Cancer Cell. 2008 Jul 8;14(1):10-21
pubmed: 18598940
Cell. 2010 Apr 16;141(2):243-54
pubmed: 20362325
Nat Commun. 2017 Jul 17;8:15981
pubmed: 28714471
Mol Cell. 2017 Oct 19;68(2):414-430.e8
pubmed: 29053959