PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.
BRCA2
DNA Repair
EXO1
FEN1
PARG
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
received:
26
06
2023
accepted:
23
01
2024
revised:
22
01
2024
medline:
18
3
2024
pubmed:
16
2
2024
entrez:
15
2
2024
Statut:
ppublish
Résumé
Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest for targeting BRCA2;p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) through loss of PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, we identify various genes involved in DNA repair to be essential for the survival of PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors of PARG loss. We provide evidence for compromised replication fork progression, DNA single-strand break repair, and Okazaki fragment processing in PARG;BRCA2;p53-deficient cells, alterations that exacerbate the effects of EXO1/FEN1 inhibition and become lethal in this context. Since this sensitivity is dependent on BRCA2 defects, we propose to target EXO1/FEN1 in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy for enhancing the effect of PARG inhibitors in homologous recombination-deficient tumors.
Identifiants
pubmed: 38360994
doi: 10.1038/s44318-024-00043-2
pii: 10.1038/s44318-024-00043-2
pmc: PMC10943112
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Glycoside Hydrolases
EC 3.2.1.-
FEN1 protein, human
EC 3.1.11.-
Flap Endonucleases
EC 3.1.-
EXO1 protein, human
EC 3.1.-
Exodeoxyribonucleases
EC 3.1.-
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1015-1042Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : 310030_179360
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : P1BEP3_195482
Organisme : EC | European Research Council (ERC)
ID : ERC-2019-AdG-883877
Organisme : Krebsliga Schweiz (Swiss Cancer League)
ID : KFS-5519-02-2022
Organisme : Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
ID : 2019.069.1
Organisme : KWF Kankerbestrijding (DCS)
ID : KWF 2017-61169
Organisme : KWF Kankerbestrijding (DCS)
ID : KWF 2020-12894
Organisme : Grantová Agentura České Republiky (GAČR)
ID : 22-00885S
Informations de copyright
© 2024. The Author(s).
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