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

C. Andronikou, K. Burdova, D. Dibitetto, C. Lieftink, E. Malzer, HJ. Kuiken, E. Gogola, A. Ray Chaudhuri, RL. Beijersbergen, H. Hanzlikova, J. Jonkers, S. Rottenberg

. 2024 ; 43 (6) : 1015-1042. [pub] 20240215

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24006860

Grant support
310030_179360 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
P1BEP3_195482 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ERC-2019-AdG-883877 EC | European Research Council (ERC)
KFS-5519-02-2022 Krebsliga Schweiz (Swiss Cancer League)
2019.069.1 Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
KWF 2017-61169 KWF Kankerbestrijding (DCS)
KWF 2020-12894 KWF Kankerbestrijding (DCS)
22-00885S Grantová Agentura České Republiky (GAČR)

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.

References provided by Crossref.org

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