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bioRxiv · 10.1101/2024.11.06.622320

Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes

Uusküla-Reimand, L.·Lee, C. A.·Oh, R. H.·Klein, Z. P.·Adler, N.·Alvi, S. A.·Langille, E.·Pasini, E.·Cheng, K. C.·Abd-Rabbo, D.·Hou, H.·Tsai, R.·Bhat, M.·Schramek, D.·Wilson, M. D.·Reimand, J.
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Abstract

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.

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Uusküla-Reimand, L., Lee, C. A., Oh, R. H., Klein, Z. P., Adler, N., Alvi, S. A., Langille, E., Pasini, E., Cheng, K. C., Abd-Rabbo, D., Hou, H., Tsai, R., Bhat, M., Schramek, D., Wilson, M. D., Reimand, J.. 2024-11-08. Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes. https://doi.org/10.1101/2024.11.06.622320

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