Andronikou, Christina; Burdova, Kamila; Dibitetto, Diego; Lieftink, Cor; Malzer, Elke; Kuiken, Hendrik J; Gogola, Ewa; Ray Chaudhuri, Arnab; Beijersbergen, Roderick L; Hanzlikova, Hana; Jonkers, Jos; Rottenberg, Sven (2024). PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair. The EMBO journal, 43(6), pp. 1015-1042. EMBO Press 10.1038/s44318-024-00043-2
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andronikou-et-al-2024-parg-deficient-tumor-cells-have-an-increased-dependence-on-exo1-fen1-mediated-dna-repair.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (6MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) |
UniBE Contributor: |
Andronikou, Christina, Dibitetto, Diego, Rottenberg, Sven |
Subjects: |
600 Technology > 610 Medicine & health 600 Technology > 630 Agriculture |
ISSN: |
1460-2075 |
Publisher: |
EMBO Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
19 Feb 2024 13:50 |
Last Modified: |
18 Mar 2024 00:15 |
Publisher DOI: |
10.1038/s44318-024-00043-2 |
PubMed ID: |
38360994 |
Uncontrolled Keywords: |
BRCA2 DNA Repair EXO1 FEN1 PARG |
BORIS DOI: |
10.48350/192958 |
URI: |
https://boris.unibe.ch/id/eprint/192958 |
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