ArticleProceedings of the National Academy of Sciences of the United States of America2022
Recurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 48 citations in OpenAlex.
- Type II topoisomerase substrate geometry revealed through combined experiment and computation.bioRxiv : the preprint server for biology · 2026Article
- A multispecies toolkit ofProceedings of the National Academy of Sciences of the United States of America · 2026Article
- IRDRM: Exploring Biological Traits and Clinical Significance in Breast Cancer Through Gene Pairs and Somatic Mutation Profiles.Interdisciplinary sciences, computational life sciences · 2026Article
- KGLAR: Deconvoluting Spatial Transcriptomics Data with Single-cell Transcriptomes through Knowledge-guided NMF and Least Angle Regression.Interdisciplinary sciences, computational life sciences · 2026Article
- Supercoiled DNA recognition and cleavage control in topoisomerase VI.Nature communications · 2026Article
- HRD-Informed Digital Histology Model for Predicting Platinum Chemo-Response and Prognosis in High-Grade Serous Ovarian Cancer.Interdisciplinary sciences, computational life sciences · 2026Article
- Targeting the E2F6-TOP2A-DKK1 axis: a novel therapeutic strategy for EMT-driven hepatocellular carcinoma progression.Frontiers in immunology · 2026Article
- Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes.Nature communications · 2025Article
- Comprehensive Mutational Landscape of Yeast Mutator Strains Reveals the Genetic Basis of Mutational Signatures in Cancer.Molecular biology and evolution · 2025Article
- Mutagenic Impact and Evolutionary Influence of Chemoradiotherapy in Hematologic Malignancies.Blood cancer discovery · 2025Article
- A tumorigenesis threshold for endogenous Myc revealed by dosage-compensation for Myc-haploinsufficiency in the absence of p53.bioRxiv : the preprint server for biology · 2025Article
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Identification of a novel RAB6A::TOP2A fusion in acute non-promyelocytic leukemia harboring t(11;17)(q13;q21) translocation.Virchows Archiv : an international journal of pathology · 2025Article
- A redefined InDel taxonomy provides insights into mutational signatures.Nature genetics · 2025Article
- Nonhypermutator Cancers Access Driver Mutations Through Reversals in Germline Mutational Bias.Molecular biology and evolution · 2025Article
- Deciphering the Foundations of Mitochondrial Mutational Spectra: Replication-Driven and Damage-Induced Signatures Across Chordate Classes.Molecular biology and evolution · 2025Article
- Advances in research on malignant tumors and targeted agents for TOP2A (Review).Molecular medicine reports · 2025Review
- Benchmarking 13 tools for mutational signature attribution, including a new and improved algorithm.Briefings in bioinformatics · 2024Article
- Mutagenic impact and evolutionary influence of radiotherapy in hematologic malignancies.bioRxiv : the preprint server for biology · 2024Article
- Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.Cancer research and treatment · 2024Review
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9 authors at 3 institutions in 2 countries.
Funding
Abstract
Topoisomerases nick and reseal DNA to relieve torsional stress associated with transcription and replication and to resolve structures such as knots and catenanes. Stabilization of the yeast Top2 cleavage intermediates is mutagenic in yeast, but whether this extends to higher eukaryotes is less clear. Chemotherapeutic topoisomerase poisons also elevate cleavage, resulting in mutagenesis. Here, we describe p.K743N mutations in human topoisomerase hTOP2α and link them to a previously undescribed mutator phenotype in cancer. Overexpression of the orthologous mutant protein in yeast generated a characteristic pattern of 2- to 4-base pair (bp) duplications resembling those in tumors with p.K743N. Using mutant strains and biochemical analysis, we determined the genetic requirements of this mutagenic process and showed that it results from trapping of the mutant yeast yTop2 cleavage complex. In addition to 2- to 4-bp duplications, hTOP2α p.K743N is also associated with deletions that are absent in yeast. We call the combined pattern of duplications and deletions ID_TOP2α. All seven tumors carrying the hTOP2α p.K743N mutation showed ID_TOP2α, while it was absent from all other tumors examined (
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