Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability

Tae-Hee Lee, Colina X. Qiao, Vladislav Kuzin, Yuepeng Shi, Marina Farkas, Zhiyan Zhao, Vijayalalitha Ramanarayanan, Tongyu Wu, Tianyi Guan, Xianzhen Zhou, David Corujo, Marcus Buschbeck, Laura Baranello and Philipp Oberdoerffer ()
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Tae-Hee Lee: Johns Hopkins University School of Medicine
Colina X. Qiao: Johns Hopkins University School of Medicine
Vladislav Kuzin: Karolinska Institutet
Yuepeng Shi: Johns Hopkins University School of Medicine
Marina Farkas: Josep Carreras Leukaemia Research Institute (IJC)
Zhiyan Zhao: Johns Hopkins University School of Medicine
Vijayalalitha Ramanarayanan: Johns Hopkins University School of Medicine
Tongyu Wu: Johns Hopkins University School of Medicine
Tianyi Guan: Johns Hopkins University School of Medicine
Xianzhen Zhou: Johns Hopkins University School of Medicine
David Corujo: Josep Carreras Leukaemia Research Institute (IJC)
Marcus Buschbeck: Josep Carreras Leukaemia Research Institute (IJC)
Laura Baranello: Karolinska Institutet
Philipp Oberdoerffer: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for DNA supercoil removal, the aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from excessive TOP1cc accumulation remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), the histone variant macroH2A1.1 facilitates TOP1cc repair factor recruitment and lesion turnover, thereby preventing DNA damage in response to transcription-associated topological stress. The alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. We propose macroH2A1 alternative splicing as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

Date: 2025
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DOI: 10.1038/s41467-025-62598-w

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