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

Christina Andronikou, Kamila Burdova, Diego Dibitetto, Cor Lieftink, Elke Malzer, Hendrik J. Kuiken, Ewa Gogola, Arnab Ray Chaudhuri, Roderick L. Beijersbergen, Hana Hanzlikova, Jos Jonkers*, Sven Rottenberg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1015-1042
Number of pages28
JournalEMBO Journal
Volume43
Issue number6
Early online date15 Feb 2024
DOIs
Publication statusPublished - 15 Mar 2024

Bibliographical note

Publisher Copyright: © The Author(s) 2024.

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