ArticleThe Journal of clinical investigation2021
RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 69 citations in OpenAlex.
- Roles of mitochondrial fusion and fission in breast cancer progression: a systematic review.World journal of surgical oncology · 2022Pooled it
- PUM3 is an essential suppressor of replication stress in homologous recombination deficient breast cancer.Nature communications · 2026Article
- The DNA/RNA Helicase SETX Maintains R-Loop Homeostasis to Promote Chemoresistance in Ovarian Cancer.Cancer science · 2026Article
- DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.Molecular cancer therapeutics · 2026Article
- Insights from three decades of BRCA1/2 modeling in mice.Nature genetics · 2026Review
- Dual roles of the DHX9 RGG domain in hybrid-dependent recruitment and suppression of 53BP1.Scientific reports · 2026Article
- Multi-omics dissection of R-loop dynamics in tumorigenesis: From transcription-replication conflict to therapeutic targets.Molecular therapy. Oncology · 2026Review
- Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168.Research square · 2026Article
- MDS/AML-associated DDX41 helicase facilitates homologous recombination repair by potentially resolving R-loops.Nucleic acids research · 2026Article
- Regulation of R-Loop Dynamics by Proteins and Long Noncoding RNAs: An Emerging Paradigm for Cancer Treatment.Cancer science · 2026Review
- EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism.Oncogene · 2025Article
- TRIM39-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer.NPJ breast cancer · 2025Article
- Participants in Transcription-Replication Conflict and Their Role in Formation and Resolution of R-Loops.International journal of molecular sciences · 2025Review
- Targeted Inhibition of cGAS/STING signaling induced by aberrant R-Loops in the nucleus pulposus to alleviate cellular senescence and intervertebral disc degeneration.Journal of nanobiotechnology · 2025Article
- The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma.Genes & development · 2025Article
- Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability.International journal of molecular sciences · 2025Review
- Mechanism of expression regulation of head-to-head overlapping protein-coding genes INO80E and HIRIP3.Communications biology · 2025Article
- Review
- A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair.Cancer research · 2025Article
- Dysregulation of R-loop homeostasis shapes the immunosuppressive microenvironment and induces malignant progression in melanoma.Apoptosis : an international journal on programmed cell death · 2025Article
Corrections and comments
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Authors and funding
27 authors at 8 institutions in 4 countries.
Funding
Abstract
Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brca1-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop-prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability.
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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.