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Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes

Author

Listed:
  • Liis Uusküla-Reimand

    (The Hospital for Sick Children, Program in Genetics and Genome Biology
    Ontario Institute for Cancer Research, Computational Biology Program)

  • Christian A. Lee

    (Ontario Institute for Cancer Research, Computational Biology Program
    University of Toronto, Department of Medical Biophysics)

  • Robin H. Oh

    (Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute
    University of Toronto, Department of Molecular Genetics)

  • Zoe P. Klein

    (Ontario Institute for Cancer Research, Computational Biology Program
    University of Toronto, Department of Molecular Genetics)

  • Nina Adler

    (Ontario Institute for Cancer Research, Computational Biology Program)

  • Sana Akhtar Alvi

    (The Hospital for Sick Children, Program in Genetics and Genome Biology)

  • Ellen Langille

    (Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute
    University of Toronto, Department of Molecular Genetics)

  • Elisa Pasini

    (University Health Network, Ajmera Transplant Centre)

  • Kevin C. L. Cheng

    (Ontario Institute for Cancer Research, Computational Biology Program
    University of Toronto, Department of Medical Biophysics)

  • Evgenija Serafimova

    (Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute)

  • Diala Abd-Rabbo

    (Ontario Institute for Cancer Research, Computational Biology Program)

  • Huayun Hou

    (The Hospital for Sick Children, Program in Genetics and Genome Biology)

  • Ricky Tsai

    (Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute)

  • Mamatha Bhat

    (University Health Network, Ajmera Transplant Centre
    University of Toronto, Division of Gastroenterology & Hepatology, Department of Medicine)

  • Daniel Schramek

    (Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute
    University of Toronto, Department of Molecular Genetics)

  • Michael D. Wilson

    (The Hospital for Sick Children, Program in Genetics and Genome Biology
    University of Toronto, Department of Molecular Genetics)

  • Jüri Reimand

    (Ontario Institute for Cancer Research, Computational Biology Program
    University of Toronto, Department of Medical Biophysics
    University of Toronto, Department of Molecular Genetics)

Abstract

Type-II topoisomerases resolve topological stress in DNA through double-strand breaks. While topoisomerases are chemotherapy targets linked to therapy-related genotoxicity, TOP2B is uniquely positioned to influence mutagenesis through its activity in non-dividing cells and sensitivity to topoisomerase poisons. To investigate this, we generated DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analyzed these for driver mutations and mutational processes across 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants, particularly at sites with evolutionary conservation, high transcription and long-range chromatin interactions. TOP2B binds driver genes such as TP53, MYC, FOXA1, and VHL, and many frequently mutated non-coding regions. We show that one non-coding TOP2B-bound element at the non-coding RNA gene RMRP drives tumor initiation and growth in vivo. Our study highlights TOP2B as a safeguard of genome integrity and a marker of mutational processes and hotspots in cancer, underscoring implications for cancer genomics research.

Suggested Citation

  • Liis Uusküla-Reimand & Christian A. Lee & Robin H. Oh & Zoe P. Klein & Nina Adler & Sana Akhtar Alvi & Ellen Langille & Elisa Pasini & Kevin C. L. Cheng & Evgenija Serafimova & Diala Abd-Rabbo & Huayu, 2025. "Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65005-6
    DOI: 10.1038/s41467-025-65005-6
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