Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea.
Department of Health Sciences and Technology, ETH Zürich, 8092, Zürich, Switzerland.
Nat Commun. 2024 Feb 15;15(1):1388. doi: 10.1038/s41467-024-45664-7.
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.
大多数具有遗传毒性的抗癌药物在 DNA 修复完整的肿瘤中失效。因此，对具有活跃 DNA 修复的细胞（特别是转录偶联核苷酸切除修复 (TC-NER)）更具毒性的药物 trabectedin 提供了治疗机会。为了挖掘 trabectedin 的潜力并为精准肿瘤学提供指导，我们需要了解该药物依赖 TC-NER 的毒性的作用机制。在这里，我们确定 trabectedin-DNA 加合物的无效 TC-NER 会形成持续的单链断裂 (SSB)，因为加合物会阻止两个连续的 NER 切口的第二个切口。我们在全基因组范围内对源自 trabectedin 损伤的第一个 NER 切口的 SSB 的 3'-羟基进行定位，记录 TC-NER。trabectedin 诱导的 SSB 主要发生在活跃基因的转录链上，并在转录起始位点附近达到峰值。在基因体之外也发现了频繁的 SSB，将 TC-NER 与启动子的发散转录连接起来。这项工作推进了 trabectedin 在精准肿瘤学中的应用，并为研究 TC-NER 和转录提供了新的思路。
