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

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, Huayun Hou, Ricky Tsai, Mamatha Bhat, Daniel Schramek, Michael D. Wilson and Jüri Reimand ()
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Liis Uusküla-Reimand: The Hospital for Sick Children, Program in Genetics and Genome Biology
Christian A. Lee: Ontario Institute for Cancer Research, Computational Biology Program
Robin H. Oh: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute
Zoe P. Klein: Ontario Institute for Cancer Research, Computational Biology Program
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
Elisa Pasini: University Health Network, Ajmera Transplant Centre
Kevin C. L. Cheng: Ontario Institute for Cancer Research, Computational Biology Program
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
Daniel Schramek: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute
Michael D. Wilson: The Hospital for Sick Children, Program in Genetics and Genome Biology
Jüri Reimand: Ontario Institute for Cancer Research, Computational Biology Program

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65005-6

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