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<p>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 <i>TP53</i>, <i>MYC</i>, <i>FOXA1</i>, and <i>VHL</i>, and many frequently mutated non-coding regions. We show that one non-coding TOP2B-bound element at&#xa0;the non-coding RNA gene <i>RMRP</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • 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,
  • Jüri Reimand

摘要

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.