한빛사논문
- 조회469
University of California, Berkeley
Kook Son 1,5, Vakil Takhaveev 2,5, Visesato Mor 1, Hobin Yu 1,3, Emma Dillier 2, Nicola Zilio 4, Nikolai J. L. Püllen 2, Dmitri Ivanov 1, Helle D. Ulrich 4, Shana J. Sturla 2 & Orlando D. Schärer 1,3
1Center for Genomic Integrity, Institute for Basic Science (IBS), 44919 Ulsan, Republic of Korea.
2Department of Health Sciences and Technology, ETH Zürich, 8092 Zürich, Switzerland.
3Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 44919 Ulsan, Republic of Korea.
4Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
5These authors contributed equally: Kook Son, Vakil Takhaveev.
Corresponding authors
Correspondence to Shana J. Sturla or Orlando D. Schärer.
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.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-16)
- 국내+국외 연구진
- 생명과학 > 생화학
관련 보도자료
- Bio통신원
- 2024. 03. 13
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