دورية أكاديمية
PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair
| العنوان: | PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair |
|---|---|
| المؤلفون: | 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 |
| المصدر: | 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 ' , EMBO Journal , vol. 43 , no. 6 , pp. 1015-1042 . https://doi.org/10.1038/s44318-024-00043-2Test |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://pure.eur.nl/en/publications/7163ae82-634d-4575-a8bd-3218c9f09754Test |
| DOI: | 10.1038/s44318-024-00043-2 |
| الإتاحة: | https://doi.org/10.1038/s44318-024-00043-2Test https://pure.eur.nl/en/publications/7163ae82-634d-4575-a8bd-3218c9f09754Test 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.pdfTest http://www.scopus.com/inward/record.url?scp=85185319701&partnerID=8YFLogxKTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.CF8A7736 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s44318-024-00043-2 |
|---|