Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency
| Autor: | Eli Rothenberg, Ke Cong, Silviana Lee, Nicholas J. Panzarino, Katherine S. Pawelczak, Neil Johnson, Sumeet Nayak, Min Peng, Arne Nedergaard Kousholt, Pamela S. VanderVere-Carozza, Jos Jonkers, Jennifer A. Calvo, Wei Ting C. Lee, John J. Turchi, John J. Krais, Sharon B. Cantor |
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| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
endocrine system diseases DNA Single-Stranded Synthetic lethality Poly(ADP-ribose) Polymerase Inhibitors Article Cell Line 03 medical and health sciences XRCC1 chemistry.chemical_compound 0302 clinical medicine PARP1 Mice Inbred NOD Replication Protein A Animals Humans skin and connective tissue diseases Homologous Recombination Molecular Biology Polymerase 030304 developmental biology 0303 health sciences Okazaki fragments biology BRCA1 Protein Cell Biology DNA Fanconi Anemia Complementation Group Proteins chemistry Drug Resistance Neoplasm PARP inhibitor biology.protein Cancer research Rad51 Recombinase Cisplatin Homologous recombination Tumor Suppressor p53-Binding Protein 1 030217 neurology & neurosurgery RNA Helicases |
| Zdroj: | Mol Cell |
| ISSN: | 1097-4164 |
| Popis: | Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions. |
| Databáze: | OpenAIRE |
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