Related Experiment Video

Updated: Jul 3, 2025

Live-Cell Imaging of Transcriptional Activity at DNA Double-Strand Breaks
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Live-Cell Imaging of Transcriptional Activity at DNA Double-Strand Breaks

Published on: September 20, 2021

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

Kook Son1, Vakil Takhaveev2, Visesato Mor1

  • 1Center for Genomic Integrity, Institute for Basic Science (IBS), 44919, Ulsan, Republic of Korea.

Nature Communications
|February 15, 2024
PubMed

Insights

Trabectedin is more toxic to cancer cells with active DNA repair. This study reveals how trabectedin forms DNA breaks during transcription-coupled nucleotide excision repair (TC-NER), advancing its use in precision oncology.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Genetics

Background:

  • Genotoxic anticancer agents are ineffective in tumors with intact DNA repair mechanisms.
  • Trabectedin exhibits enhanced toxicity in cells with active DNA repair, particularly transcription-coupled nucleotide excision repair (TC-NER).

Purpose of the Study:

  • To elucidate the mechanism of trabectedin's TC-NER-dependent toxicity.
  • To guide the precise application of trabectedin in cancer therapy.

Main Methods:

  • Genome-wide mapping of single-strand breaks (SSBs) induced by trabectedin.
  • Analysis of TC-NER pathway engagement with trabectedin-DNA adducts.

Main Results:

  • Abortive TC-NER of trabectedin-DNA adducts leads to persistent SSBs by blocking NER incisions.
  • Trabectedin-induced SSBs predominantly occur on transcribed strands of active genes, near transcription start sites.
  • SSBs are also observed outside gene bodies, linked to divergent transcription.

Conclusions:

  • This research clarifies trabectedin's mechanism of action, highlighting its reliance on TC-NER.
  • The findings support trabectedin's role in precision oncology for treating specific tumor types.
  • This study provides a framework for investigating TC-NER and transcription dynamics.

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