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

Kook Son, Vakil Takhaveev, Visesato Mor, Hobin Yu, Emma Dillier, Nicola Zilio, Nikolai J. L. Püllen, Dmitri Ivanov, Helle D. Ulrich, Shana J. Sturla () and Orlando D. Schärer ()
Additional contact information
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)
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)

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45664-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45664-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45664-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().