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Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability

Author

Listed:
  • Tae-Hee Lee

    (Johns Hopkins University School of Medicine)

  • Colina X. Qiao

    (Johns Hopkins University School of Medicine
    Johns Hopkins Bloomberg School of Public Health
    Johns Hopkins University)

  • Vladislav Kuzin

    (Karolinska Institutet)

  • Yuepeng Shi

    (Johns Hopkins University School of Medicine
    Johns Hopkins Bloomberg School of Public Health)

  • Marina Farkas

    (Josep Carreras Leukaemia Research Institute (IJC))

  • Zhiyan Zhao

    (Johns Hopkins University School of Medicine)

  • Vijayalalitha Ramanarayanan

    (Johns Hopkins University School of Medicine
    Johns Hopkins Bloomberg School of Public Health
    UMass Chan Medical School)

  • Tongyu Wu

    (Johns Hopkins University School of Medicine
    Johns Hopkins Bloomberg School of Public Health
    University of Pittsburgh)

  • Tianyi Guan

    (Johns Hopkins University School of Medicine)

  • Xianzhen Zhou

    (Johns Hopkins University School of Medicine
    Johns Hopkins Bloomberg School of Public Health
    St Anne’s College)

  • David Corujo

    (Josep Carreras Leukaemia Research Institute (IJC))

  • Marcus Buschbeck

    (Josep Carreras Leukaemia Research Institute (IJC)
    Germans Trias i Pujol Research Institute (IGTP))

  • Laura Baranello

    (Karolinska Institutet)

  • Philipp Oberdoerffer

    (Johns Hopkins University School of Medicine)

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.

Suggested Citation

  • 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 & L, 2025. "Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62598-w
    DOI: 10.1038/s41467-025-62598-w
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