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

Autor: Son K; Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea., Takhaveev V; Department of Health Sciences and Technology, ETH Zürich, 8092, Zürich, Switzerland., Mor V; Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea., Yu H; Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea.; Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 44919, Ulsan, Republic of Korea., Dillier E; Department of Health Sciences and Technology, ETH Zürich, 8092, Zürich, Switzerland., Zilio N; Institute of Molecular Biology (IMB), 55128, Mainz, Germany., Püllen NJL; Department of Health Sciences and Technology, ETH Zürich, 8092, Zürich, Switzerland., Ivanov D; Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea., Ulrich HD; Institute of Molecular Biology (IMB), 55128, Mainz, Germany., Sturla SJ; Department of Health Sciences and Technology, ETH Zürich, 8092, Zürich, Switzerland. sturlas@ethz.ch., Schärer OD; Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea. orlando.scharer@ibs.re.kr.; Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 44919, Ulsan, Republic of Korea. orlando.scharer@ibs.re.kr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 15; Vol. 15 (1), pp. 1388. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1038/s41467-024-45664-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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