Digital illustration of DNA strands and cancer cells symbolizing targeted cancer therapy

DNA Damage and Cancer Drugs: Can We Turn Cellular Weakness Into Strength?

Lena Voss in Health & Wellness August 2025 • 4 min read.

"New research explores how common cancer drugs induce DNA damage and genome instability, potentially offering new avenues for targeted cancer therapies."

Cancer treatment often relies on small molecules that disrupt DNA metabolism. Trabectedin (ET743), initially derived from a sea squirt, and its synthetic derivative lurbinectedin (PM01183), are examples of such drugs. These drugs are used to treat advanced soft tissue sarcoma and platinum-sensitive ovarian cancer.

One of the primary mechanisms of these drugs involves inhibiting transcription—the process by which DNA is read to create RNA. They preferentially bind to specific DNA sequences and can prevent transcription factors from binding to chromatin. Moreover, they induce the degradation of RNA polymerase II (RNAPII), a critical enzyme in transcription.

Cancer cells are often associated with genome instability. R-loops, structures consisting of an RNA-DNA hybrid and displaced single-stranded DNA, can be a significant source of this instability. While R-loops can play physiological roles, they can also lead to DNA damage and replication stress, linking them to neurodegenerative disorders and cancer.

How Trabectedin and Lurbinectedin Affect DNA and Genome Stability

Digital illustration of DNA strands and cancer cells symbolizing targeted cancer therapy

Recent research has shown that trabectedin and lurbinectedin cause transcription-dependent replication stress and genome instability. These drugs induce RNA-DNA hybrid-dependent DNA damage in HeLa cells, leading to replication impairment. High levels of R-loops increase the sensitivity of cells to trabectedin, indicating a critical role for these structures in the cellular response to the drugs.

Furthermore, trabectedin leads to transcription-dependent accumulation of FANCD2 foci, a key protein in the Fanconi Anemia (FA) pathway, which is involved in DNA repair. This accumulation is suppressed by the overexpression of RNase H1, an enzyme that degrades the RNA component of RNA-DNA hybrids. These findings suggest that R-loops are crucial in the mechanism of action of these drugs.

R-loops and DNA Damage: Drugs like trabectedin and lurbinectedin induce DNA damage and genome instability by affecting RNA-DNA hybrids.
Transcription Dependency: The drugs' impact on DNA is closely linked to transcription processes.
FANCD2 Foci Accumulation: Trabectedin leads to increased FANCD2 foci, which are suppressed by RNase H1 overexpression.
Evolutionary Conservation: The effects of these drugs are seen in both human and yeast cells, indicating an evolutionarily conserved mechanism.

To further investigate the impact on DNA replication, DNA combing was used. The results showed that at concentrations that didn't affect replication fork velocity, trabectedin increased fork stalling, as measured by fork asymmetry. Inhibiting transcription with cordycepin abolished the difference in fork asymmetry between treated and untreated samples, indicating a link between transcription and fork stalling.

Implications for Future Cancer Therapies

This research provides a new understanding of how trabectedin and lurbinectedin work, linking their activity to transcription and R-loop formation. These insights suggest that targeting R-loops could be a viable strategy for developing new anticancer agents. Given that R-loops are present throughout the genome, drugs that can effectively act on these structures may enhance their therapeutic efficacy, opening new possibilities for treating specific cancers.

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This article is based on research published under:

DOI-LINK: 10.1158/1541-7786.mcr-18-0575, Alternate LINK

Title: The Antitumor Drugs Trabectedin And Lurbinectedin Induce Transcription-Dependent Replication Stress And Genome Instability

Subject: Cancer Research

Journal: Molecular Cancer Research

Publisher: American Association for Cancer Research (AACR)

Authors: Emanuela Tumini, Emilia Herrera-Moyano, Marta San Martín-Alonso, Sonia Barroso, Carlos M. Galmarini, Andrés Aguilera

Published: 2019-03-01

Everything You Need To Know

What are trabectedin and lurbinectedin, and how do they work in cancer treatment?

Trabectedin and lurbinectedin are small molecule drugs used in cancer treatment, specifically for advanced soft tissue sarcoma and platinum-sensitive ovarian cancer. These drugs disrupt DNA metabolism. They work by inhibiting transcription, the process of reading DNA to create RNA. They bind to specific DNA sequences, preventing transcription factors from attaching to chromatin and causing the degradation of RNA polymerase II (RNAPII), an essential enzyme in transcription.

What is genome instability, and why is it significant in the context of cancer?

Genome instability refers to the accumulation of DNA damage and mutations within a cell's genetic material. In the context of cancer, genome instability is a hallmark of cancer cells and is often associated with cancer development and progression. R-loops, which are RNA-DNA hybrids, contribute to this instability, leading to replication stress and DNA damage. Trabectedin and lurbinectedin exacerbate this instability by affecting these R-loops.

How do trabectedin and lurbinectedin affect DNA and genome stability?

The research indicates that trabectedin and lurbinectedin induce DNA damage and genome instability by affecting RNA-DNA hybrids, specifically R-loops. The drugs cause transcription-dependent replication stress, leading to increased fork stalling. High levels of R-loops increase the cells' sensitivity to the drugs. The drugs also cause the accumulation of FANCD2 foci, a protein in the Fanconi Anemia (FA) pathway, which is involved in DNA repair. This process is suppressed by RNase H1 overexpression, indicating that R-loops are central to the mechanism of action of these drugs.

What is the role of transcription in the context of this research?

Transcription is the process where DNA is read to create RNA, facilitated by RNA polymerase II (RNAPII). Drugs like trabectedin and lurbinectedin interfere with transcription by binding to DNA and inhibiting the attachment of transcription factors to chromatin, ultimately leading to RNAPII degradation. These processes are important because the drugs' impact on DNA and genome stability is closely connected to these transcription processes. Inhibiting transcription with cordycepin abolishes the differences in fork asymmetry between treated and untreated samples.

What are the implications of this research for future cancer therapies?

The research suggests that targeting R-loops could be a potential strategy for developing new anticancer agents. Given that R-loops are present throughout the genome, drugs that can effectively act on these structures may enhance therapeutic efficacy, opening new possibilities for treating specific cancers. By understanding and controlling the function of R-loops, new cancer treatments may be developed that improve the effectiveness of existing cancer drugs such as trabectedin and lurbinectedin.