DNA topoisomerase I
Topoisomerase 1 Dmel_CG6146 (Wikidata: Q29814717) is the Drosophila melanogaster ortholog of human DNA topoisomerase I (TOP1), encoded by CG6146. topoisomerase I resolves the topological strain that accumulates ahead of replication forks and transcribing polymerases: it cleaves one strand of the duplex, forming a transient covalent intermediate — the TOP1 cleavage complex (TOP1cc), in which an active-site tyrosine is linked to the 3′ end of the nick — allows the DNA to rotate about the intact strand, and then reseals it.
Topoisomerase 1 Dmel_CG6146 (Wikidata: Q29814717) is the Drosophila melanogaster ortholog of human DNA topoisomerase I (TOP1), encoded by CG6146. topoisomerase I resolves the topological strain that accumulates ahead of replication forks and transcribing polymerases: it cleaves one strand of the duplex, forming a transient covalent intermediate — the TOP1 cleavage complex (TOP1cc), in which an active-site tyrosine is linked to the 3′ end of the nick — allows the DNA to rotate about the intact strand, and then reseals it. Unlike type II enzymes it needs no ATP, since the energy of the broken phosphodiester bond is stored in the protein–DNA link and recovered on religation. The reaction is essential in both directions of gene expression, and without it transcription generates positive supercoils ahead and negative supercoils behind that stall the polymerase and promote R-loop formation.
The enzyme is one of the most validated antitumor drug targets, for a reason that lies in its intermediate rather than its function. camptothecin-class inhibitors do not block catalysis; they bind at the enzyme–DNA interface and prevent religation, converting a normal transient intermediate into a persistent protein-linked single-strand break. Double-strand breaks arise secondarily, when a replication fork or transcription complex collides with the trapped complex or during its processing — which makes the drugs S-phase selective and makes exposure time, rather than peak concentration, the determinant of cell kill. Cells defend themselves by removing the adduct: tyrosyl-DNA phosphodiesterase 1 (TDP1) hydrolyzes the tyrosyl–DNA bond, and its loss sensitizes cells to these agents, while hereditary TDP1 deficiency causes a neurodegenerative ataxia, showing that trapped complexes accumulate in non-dividing neurons too.
The Drosophila protein is highly conserved with its human counterpart and has served as a tractable genetic and biochemical model for TOP1 function, inhibitor sensitivity and the DNA damage response — a role that depends on that conservation, since the trapping mechanism and its repair are shared across the eukaryotes.
Rebuilt from PubMed 10 Sept 2026 · no new papers today
Where the papers sit
16 papers study dna topoisomerase i directly. Those 16 are one subject: Topoisomerase I Cancer Therapies. Drug design is moving beyond conventional camptothecins toward TOP1 degraders, TOP1/PARP1 or TOP1/II dual inhibitors, and conjugates with improved delivery. Nanotubes, bioorthogonal release and oral formulations recur alongside efforts to link TOP1 activity to tumor inflammation. No way of splitting those 16 scores better than chance. 1 paradigm shift follows.
TOP1-directed therapy can work by degrading the enzyme, not only by inhibiting its catalytic activity
The aromatic camptothecin degrader study and the SN-38–nitrogen mustard conjugate study both depart from the usual inhibitor-only design: SN-38-A2 was engineered as a proteasome-dependent TOP1 degrader while retaining TOP1–DNA binding, and MN33-47/MN33-63 were found to inhibit TOP1 while also promoting its degradation. Together, these independent systems indicate that eliminating TOP1 can be an active therapeutic mechanism alongside catalytic inhibition, changing TOP1 drug development from optimizing enzyme blockade alone to designing agents that remove the target protein as well. 42378337Jun 41865567Mar
Recent Findings on DNA topoisomerase I
The studies converge on improving the therapeutic performance of topoisomerase I inhibitor payloads through delivery, molecular redesign, and combination strategies rather than relying on unmodified compounds. Surface-confined hafnium nanoscale metal–organic layers enabled radiotherapy-triggered release of Exatecan, achieving an intratumoral release value of 568 nM·Gy−1 with radiosensitization and tumor-growth suppression, while SN-38-based bifunctional molecules improved solubility and combined topoisomerase I inhibition, degradation, and DNA crosslinking 42468144Jul41865567Mar. Other approaches addressed resistance or pharmacological limitations by converting camptothecins into proteasome-dependent TOP1 degraders, combining SN-38 delivery with PERK inhibition to suppress adaptive stress and Wnt/β-catenin signaling, and developing FRα-targeted TOP1 inhibitor ADCs 42378337Jun42030933Apr42007996Apr. This translational direction is accompanied by greater attention to formulation and quality control, including analytical methods that prevent thermal payload detachment or lactone-ring opening from causing inaccurate ADC drug-to-antibody ratio measurements 42237689Jun.
This body of work broadly supports TOP1 inhibition as a route to DNA damage, cell-cycle disruption, apoptotic process activation, and tumor suppression, while expanding beyond topotecan through new chemical scaffolds and repair-targeted combinations. A TDP1 inhibitor enhanced topotecan activity by increasing DNA damage and apoptosis in cervical cancer models, whereas flavonolactam, fused pyridopyrimidine, and sophoridine- or matrine-derived compounds produced TOP1 inhibition with antitumor effects in colorectal, lung, ovarian, gastric, and other cancer models 42012226Apr41934689Apr41922123Apr41812411Mar. The downstream responses were not uniform: some candidates induced G2/M arrest, others G0/G1 arrest, and the topotecan combination additionally suggested ferroptosis; one benzothiophene derivative activated the cGAS-STING pathway alongside apoptosis 42012226AprPMID 4183468941844052Mar. The field is therefore moving toward multifunctional TOP1-directed agents that combine enzymatic inhibition with DNA-repair blockade or immune signaling, although reported potency and selectivity vary substantially across compounds and assay systems.
The bladder cancer-focused studies converge on intensifying TOP1-associated DNA damage while overcoming resistance or improving the exposure and immunological effects of the treatment. A united TOP1/PARP1 inhibitor was designed to generate single-strand breaks while blocking their repair, converting them into lethal double-strand breaks and overcoming cisplatin resistance; its lead compound produced a tumor-growth inhibition rate of 65.7% 42504569Jul. A separate camptothecin derivative targeting TOP1/DDX5 required Soluplus-based dispersion to overcome poor solubility, increasing solubility 389-fold and oral bioavailability 14.38-fold, while activating cGAS-STING, damage-associated molecular pattern release, and immunogenic cell death; the formulation achieved 99.84% tumor-growth inhibition in vivo 42437626Jul. Complementary anthrafuran research broadened the chemical strategy by identifying a DNA-intercalating dual TOP1/TOP2 inhibitor that retained activity against P-glycoprotein- and TP53-mediated multidrug resistance, caused apoptosis without substantial reactive oxygen species generation, and showed that intracellular accumulation can determine cellular efficacy despite similar in vitro target interactions 41905253Mar.
Written from 16 PubMed abstracts, each one cited by PMID above. Published: 2026-06-16. Last written: 2026-08-26 by GPT. Corrections: 2026-08-08 by GPT. Drafted by language models from published abstracts; not medical advice.