Paper

Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes

Reimand, Jüri, Adler, Nina, Wilson, Michael D, Bhat, Mamatha, Hou, Huayun, Lee, Christian A, Klein, Zoe P, Tsai, Ricky, Sana Akhtar Alvi, Langille, Ellen, Oh, Robin H, Schramek, Daniel, Pasini, Elisa, Cheng, Kevin Cl, Abd-Rabbo, Diala, Uusküla-Reimand, Liis

2024

Overview

Type-II topoisomerases resolve topological stress in DNA through controlled double-strand breaks. While TOP2A is a chemotherapy target in proliferating cells, the ubiquitously expressed TOP2B is a potential off-target. Here we explore roles of TOP2B in mutagenesis by generating DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analysing these maps for driver mutations and mutational processes in 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants (SVs), especially at evolutionary conserved sites displaying high transcription and long-range chromatin interactions. TOP2B binding underlies SVs and hotspot mutations in cancer-driving genes such as TP53, MYC, FOXA1, and VHL, and many cis-regulatory elements. We show that the TOP2B-bound mutational hotspot at RMRP drives tumor initiation and growth in vivo. These data highlight TOP2B as a protector of the genome from topological challenges whose aberrant activity promotes driver and passenger mutations in cancer genomes.Competing Interest StatementThe authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Cancer / Cancer Biology / Chemotherapy / Chromatin / DNA damage / DNA topoisomerase / Evolutionary conservation / Gene mapping / Genomes / Mutagenesis / Mutation / Mutation hot spots / Myc protein / p53 Protein / Regulatory sequences