ArticleCancer research2024
R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- The role of R-loops-mediated epigenetic regulation in genome stability maintenance and disease pathogenesis: a systematic review.Epigenetics · 2026Pooled it
- DNA polymerase I and DnaE mediate RNA-templated DNA synthesis over embedded ribonucleotides.Nucleic acids research · 2026Article
- The DNA/RNA Helicase SETX Maintains R-Loop Homeostasis to Promote Chemoresistance in Ovarian Cancer.Cancer science · 2026Article
- TargetingGenes & development · 2026Article
- Nonsense-Mediated RNA Decay Is a Targetable Vulnerability in Splicing Factor Mutant Myeloid Neoplasms by Enhancing R-Loop Accumulation and DNA Damage.Cancer research · 2026Article
- R-loops and D-loops: a delicate balance in genomic stability and instability.Cell communication and signaling : CCS · 2026Review
- Polymerase face-off: emerging concepts in transcription-replication coordination.EMBO reports · 2026Review
- Integrative Analysis Reveals Conserved R-Loop Features in Mouse Embryonic Stem Cells.Epigenomes · 2026Article
- A Yeast-Based High-Throughput Screening Platform for the Discovery of Novel pre-mRNA Splicing Modulators.ACS chemical biology · 2026Article
- Transcription termination counteracts DNA damage after WEE1 inhibition.Nucleic acids research · 2026Article
- SF3B1 Phosphorylation Prompts U2AF2 Dissociation for Widespread Control of pre-mRNA Splicing.bioRxiv : the preprint server for biology · 2026Article
- MTUS2-AS1 suppression promotes DDX5 protein degradation to enhance the sensitivity of PARP inhibitors in BRCA-wild triple negative breast cancer.International journal of biological sciences · 2026Article
- DNA polymerase I is an efficient reverse transcriptase that mediates RNA-templated DNA repair synthesis.bioRxiv : the preprint server for biology · 2025Article
- Prpf4 sequentially regulates the expansion and maturation of erythrocyte through distinct mechanisms.Cell death discovery · 2025Article
- Emerging roles of RNA:DNA hybrid regulation by mammalian ribonuclease H2 in replication stress and cancer.Journal of cell science · 2025Review
- A Yeast-Based High-Throughput Screening Platform for the Discovery of Novel pre-mRNA Splicing Modulators.bioRxiv : the preprint server for biology · 2025Article
- Splicing Factor Mutations in Chronic Myelomonocytic Leukemia: Biological Consequences and Therapeutic Implications.Current hematologic malignancy reports · 2025Review
- m6A modification in R-loop homeostasis: a potential target for cancer therapeutics.NAR cancer · 2025Review
- Article
- Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
30 authors at 9 institutions in 4 countries.
Funding
Abstract
RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer. SIGNIFICANCE: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
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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.