IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45664-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45664-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-45664-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Namrata Kumar & Arjan F. Theil & Vera Roginskaya & Yasmin Ali & Michael Calderon & Simon C. Watkins & Ryan P. Barnes & Patricia L. Opresko & Alex Pines & Hannes Lans & Wim Vermeulen & Bennett Houten, 2022. "Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Diana A. Llerena Schiffmacher & Shun-Hsiao Lee & Katarzyna W. Kliza & Arjan F. Theil & Masaki Akita & Angela Helfricht & Karel Bezstarosti & Camila Gonzalo-Hansen & Haico Attikum & Matty Verlaan-de Vr, 2024. "The small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Alba Muniesa-Vargas & Carlota Davó-Martínez & Cristina Ribeiro-Silva & Melanie van der Woude & Karen L. Thijssen & Ben Haspels & David Häckes & Ülkem U. Kaynak & Roland Kanaar & Jurgen A. Marteijn & A, 2024. "Persistent TFIIH binding to non-excised DNA damage causes cell and developmental failure," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Charlotte Blessing & Katja Apelt & Diana Heuvel & Claudia Gonzalez-Leal & Magdalena B. Rother & Melanie Woude & Román González-Prieto & Adi Yifrach & Avital Parnas & Rashmi G. Shah & Tia Tyrsett Kuo &, 2022. "XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45664-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.