Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes
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.
Authors
- Huayun Hou (ORCID: https://orcid.org/0000-0003-3971-1427)
- Sana Alvi (ORCID: https://orcid.org/0000-0003-4308-8244)
- Elisa Pasini (ORCID: https://orcid.org/0000-0002-1547-7077)
- Daniel Schramek (ORCID: https://orcid.org/0000-0001-9977-2104)
- Diala Abd-Rabbo
- Ellen Langille (ORCID: https://orcid.org/0000-0002-3616-3616)
- Michael D. Wilson (ORCID: https://orcid.org/0000-0002-4015-3066)
- Christian A. Lee
- Robin H. Oh (ORCID: https://orcid.org/0000-0002-3408-6143)
- Liis Uusküla-Reimand (ORCID: https://orcid.org/0000-0002-5322-5524)
- Evgenija Serafimova
- Mamatha Bhat (ORCID: https://orcid.org/0000-0003-1960-8449)
- Nina Adler (ORCID: https://orcid.org/0000-0002-0297-2706)
- Ricky Tsai (ORCID: https://orcid.org/0000-0001-5916-6978)
- Jüri Reimand (ORCID: https://orcid.org/0000-0002-2299-2309)
- Zoe P. Klein (ORCID: https://orcid.org/0009-0000-0228-5503)
- Kevin C.L. Cheng (ORCID: https://orcid.org/0009-0008-8789-6378)
Institutions
- Ontario Institute for Cancer Research (CA)
- Mount Sinai Hospital (CA)
- University Health Network (CA)
- University of Toronto (CA)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Hospital for Sick Children (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1038/s41467-025-65005-6
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research Society
- Government of Ontario
- Canada Research Chairs
- Eesti Teadusagentuur
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada