ArticleMolecular cell2021
Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.
Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 224 papers.
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Who cites it
224 citing papers in PubMed, 302 citations in OpenAlex.
- Expanding the therapeutic scope of PARP inhibitors in breast cancer: current indications and future directions.The Journal of clinical investigation · 2026Review
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Replication stress in cancer: origins, consequences and therapeutic opportunities.Nature reviews. Cancer · 2026Review
- Sensitizing Colorectal Cancer to PARP Inhibitors: Biomarkers, Mechanisms, and Combination Strategies.International journal of molecular sciences · 2026Review
- Article
- STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation.NAR cancer · 2026Article
- PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer.The Journal of clinical investigation · 2026Article
- FANCA-dependent FEN1 recruitment suppresses transcription-replication conflicts and PARPi sensitivity.Molecular cell · 2026Article
- Molecular Characterization of PARP Inhibitor Response Reveals Co-Targeting Strategies in Advanced Prostate Cancer.Cancers · 2026Article
- Literature-informed gene extraction and ranking for multimodal data fusion.Briefings in bioinformatics · 2026Article
- G-quadruplex homeostasis is a determinant of PARP inhibitor toxicity in BRCA2-deficient cells.Nature communications · 2026Article
- STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation.bioRxiv : the preprint server for biology · 2026Article
- Prognostic, Predictive, and Clinical Relevance of DNA Damage Repair Alterations in Biliary Tract Cancers.Cancers · 2026Review
- Article
- FET proteins and PARylation-dependent condensates promote replication fork reversal and genome stability.Nature communications · 2026Article
- CHD1L maintains genome integrity by facilitating okazaki fragment maturation.Nucleic acids research · 2026Article
- Mechanisms of PARP Inhibitor Resistance: From Replication Gap Biology and Transcription-Replication Conflicts to PROTAC-Based Next-Generation Strategies.Environmental and molecular mutagenesis · 2026Review
- Tilting the balance of life and death: navigating DNA replication stress in cancer therapy.Experimental & molecular medicine · 2026Review
- Nucleophagy removes cytotoxic trapped PARP1.Nature cell biology · 2026Article
- Loss of CHTF18-RFC2/5 leads to replicative gaps and sensitivity to PARP inhibitors.NAR cancer · 2026Article
164 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 7 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.