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Updated: May 9, 2025

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
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When DNA Repair Backfires - Trabectedin Induces DNA Breaks in Active Genes

Vakil Takhaveev1, Kook Son2, Visesato Mor2

  • 1Department of Health Sciences and Technology, ETH Zürich, CH-8092 Zürich, Switzerland. vakil.takhaveev@hest.ethz.ch.

Chimia
|May 2, 2025
PubMed

Insights

Trabectedin is a potent anticancer drug that targets cancer cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER). This study visualizes TC-NER genome-wide, revealing how trabectedin induces DNA breaks in active genes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Anticancer drug efficacy is often limited by tumor DNA repair mechanisms.
  • Trabectedin, a marine natural product, exhibits enhanced lethality in cancer cells with active DNA repair, particularly transcription-coupled nucleotide excision repair (TC-NER).

Purpose of the Study:

  • To elucidate the mechanism by which trabectedin's toxicity depends on TC-NER.
  • To enable genome-wide visualization of TC-NER by mapping trabectedin-induced DNA damage.

Main Methods:

  • Mapping of 3'-hydroxyl groups of single-strand breaks (SSBs) resulting from the initial NER incision at trabectedin-DNA adducts.
  • Genome-wide visualization of TC-NER activity.

Main Results:

  • Incomplete TC-NER of trabectedin-DNA adducts leads to persistent SSBs.
  • Trabectedin-DNA adducts impede the second incision step in NER.
  • Trabectedin-induced SSBs are primarily located on transcribed strands of active genes, near transcription start sites.

Conclusions:

  • This study provides a method for genome-wide visualization of TC-NER.
  • Findings offer insights into trabectedin's mechanism of action and its potential in precision oncology.
  • The research contributes to understanding TC-NER and transcription regulation in cancer therapy.
Keywords:
DNA repairGenomicsPrecision oncologyTrabectedin

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