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

0585313 - ÚMG 2025 RIV US eng J - Journal Article
Andronikou, C. - Burdová, Kamila - Dibitetto, D. - Lieftink, C. - Malzer, E. - Kuiken, H. J. - Gogola, E. - Chaudhuri, A. R. - Beijersbergen, R. L. - Hanzlíková, Hana - Jonkers, J. - Rottenberg, S.
PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.
EMBO Journal. Roč. 43, č. 6 (2024), s. 1015-1042. ISSN 0261-4189. E-ISSN 1460-2075
R&D Projects: GA ČR GA22-00885S
Institutional support: RVO:68378050
Keywords : tumor cells * PARG * DNA Repair * BRCA2
OECD category: Cell biology
Impact factor: 11.4, year: 2022
Method of publishing: Open access
https://www.embopress.org/doi/full/10.1038/s44318-024-00043-2

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.
Permanent Link: https://hdl.handle.net/11104/0353023