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Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes

Author

Listed:
  • Kook Son

    (Institute for Basic Science (IBS))

  • Vakil Takhaveev

    (ETH Zürich)

  • Visesato Mor

    (Institute for Basic Science (IBS))

  • Hobin Yu

    (Institute for Basic Science (IBS)
    Ulsan National Institute of Science and Technology (UNIST))

  • Emma Dillier

    (ETH Zürich)

  • Nicola Zilio

    (Institute of Molecular Biology (IMB))

  • Nikolai J. L. Püllen

    (ETH Zürich)

  • Dmitri Ivanov

    (Institute for Basic Science (IBS))

  • Helle D. Ulrich

    (Institute of Molecular Biology (IMB))

  • Shana J. Sturla

    (ETH Zürich)

  • Orlando D. Schärer

    (Institute for Basic Science (IBS)
    Ulsan National Institute of Science and Technology (UNIST))

Abstract

Most genotoxic anticancer agents fail in tumors with intact DNA repair. Therefore, trabectedin, anagent more toxic to cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER), provides therapeutic opportunities. To unlock the potential of trabectedin and inform its application in precision oncology, an understanding of the mechanism of the drug’s TC-NER-dependent toxicity is needed. Here, we determine that abortive TC-NER of trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) as the adducts block the second of the two sequential NER incisions. We map the 3’-hydroxyl groups of SSBs originating from the first NER incision at trabectedin lesions, recording TC-NER on a genome-wide scale. Trabectedin-induced SSBs primarily occur in transcribed strands of active genes and peak near transcription start sites. Frequent SSBs are also found outside gene bodies, connecting TC-NER to divergent transcription from promoters. This work advances the use of trabectedin for precision oncology and for studying TC-NER and transcription.

Suggested Citation

  • Kook Son & Vakil Takhaveev & Visesato Mor & Hobin Yu & Emma Dillier & Nicola Zilio & Nikolai J. L. Püllen & Dmitri Ivanov & Helle D. Ulrich & Shana J. Sturla & Orlando D. Schärer, 2024. "Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45664-7
    DOI: 10.1038/s41467-024-45664-7
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    References listed on IDEAS

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    1. Cristina Ribeiro-Silva & Mariangela Sabatella & Angela Helfricht & Jurgen A. Marteijn & Arjan F. Theil & Wim Vermeulen & Hannes Lans, 2020. "Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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