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PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

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Title: PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair
Authors: 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
Source: Andronikou, C, Burdova, K, Dibitetto, D, Lieftink, C, Malzer, E, Kuiken, H J, Gogola, E, Ray Chaudhuri, A, Beijersbergen, R L, Hanzlikova, H, Jonkers, J & Rottenberg, S 2024, 'PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair', The EMBO journal, vol. 43, no. 6, pp. 1015-1042. https://doi.org/10.1038/s44318-024-00043-2
Publication Year: 2024
Subject Terms: /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being
Description: 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.
Document Type: article in journal/newspaper
File Description: application/pdf
Language: English
Relation: info:eu-repo/semantics/altIdentifier/pmid/38360994; info:eu-repo/semantics/altIdentifier/pissn/0261-4189; info:eu-repo/semantics/altIdentifier/eissn/1460-2075
DOI: 10.1038/s44318-024-00043-2
Availability: https://pure.eur.nl/en/publications/7163ae82-634d-4575-a8bd-3218c9f09754
https://doi.org/10.1038/s44318-024-00043-2
https://pure.eur.nl/ws/files/137029215/andronikou-et-al-2024-parg-deficient-tumor-cells-have-an-increased-dependence-on-exo1-fen1-mediated-dna-repair.pdf
https://www.scopus.com/pages/publications/85185319701
Rights: info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/
Accession Number: edsbas.CFEB1113
Database: BASE
Description
Abstract: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.
DOI:10.1038/s44318-024-00043-2