ArticleMolecular cancer research : MCR2021
R-Loop-Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin.
Article in Molecular cancer research : MCR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
What it found
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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
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- The role of R-loops-mediated epigenetic regulation in genome stability maintenance and disease pathogenesis: a systematic review.Epigenetics · 2026Pooled it
- Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors.The oncologist · 2024Trial
- Pharmacological chromatin remodeling enhances response to estrogen therapy in ERMolecular oncology · 2026Article
- Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic ductal adenocarcinoma.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2026Article
- Base excision repair within structure-forming repeat sequences and its impact on cancer and other diseases.NAR cancer · 2025Review
- Screening FDA-Approved Oncology Drugs with Three-Dimensional Spheroids Identifies Romidepsin as a Therapeutic Candidate for Osteosarcoma.Cancer research communications · 2025Article
- Article
- Looping forward: exploring R-loop processing and therapeutic potential.FEBS letters · 2025Review
- Mechanisms underlining R-loop biology and implications for human disease.Frontiers in cell and developmental biology · 2025Review
- Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations.International journal of molecular sciences · 2024Article
- M6A-methylated circPOLR2B forms an R-loop and regulates the biological behavior of glioma stem cells through positive feedback loops.Cell death & disease · 2024Article
- Article
- R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance.International journal of molecular sciences · 2023Review
- The chromatin-associated RNAs in gene regulation and cancer.Molecular cancer · 2023Review
- Article
- Sources, resolution and physiological relevance of R-loops and RNA-DNA hybrids.Nature reviews. Molecular cell biology · 2022Review
- Article
- Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.Frontiers in molecular biosciences · 2021Review
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 4 countries.
Funding
Abstract
Histone deacetylase inhibitors (HDACi) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action (MOA). Multiple activities of HDACis have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression. Here, using a clinically relevant exposure duration, we established DNA damage as the dominant signature using the NCI-60 cell line database and then focused on the mechanism by which hyperacetylation induces DNA damage. We identified accumulation of DNA-RNA hybrids (R-loops) following romidepsin-induced histone hyperacetylation, with single-stranded DNA (ssDNA) breaks detected by single-cell electrophoresis. Our data suggest that transcription-coupled base excision repair (BER) is involved in resolving ssDNA breaks that, when overwhelmed, evolve to lethal dsDNA breaks. We show that inhibition of BER proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R-loops as a consequence of romidepsin-mediated histone hyperacetylation. We believe that the insights provided will inform design of more effective combination therapy with HDACis for treatment of solid tumors. IMPLICATIONS: Key HDAC inhibitor mechanisms of action remain unknown; we identify accumulation of DNA-RNA hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first step toward cell death.
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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.