American Association for Cancer Research
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15417786mcr180575-sup-202854_2_supp_5154825_phx4w4.doc (46 kB)

Supplementary information from The Antitumor Drugs Trabectedin and Lurbinectedin Induce Transcription-Dependent Replication Stress and Genome Instability

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posted on 2023-04-03, 16:45 authored by Emanuela Tumini, Emilia Herrera-Moyano, Marta San Martín-Alonso, Sonia Barroso, Carlos M. Galmarini, Andrés Aguilera

Supplementary information contains the supplementary material and methods and the legends of the supplemetary figures.

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European Research Council

Spanish Ministry of Economy and Competitiveness

FEDER

PharmaMar

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ARTICLE ABSTRACT

R-loops are a major source of replication stress, DNA damage, and genome instability, which are major hallmarks of cancer cells. Accordingly, growing evidence suggests that R-loops may also be related to cancer. Here we show that R-loops play an important role in the cellular response to trabectedin (ET743), an anticancer drug from marine origin and its derivative lurbinectedin (PM01183). Trabectedin and lurbinectedin induced RNA–DNA hybrid-dependent DNA damage in HeLa cells, causing replication impairment and genome instability. We also show that high levels of R-loops increase cell sensitivity to trabectedin. In addition, trabectedin led to transcription-dependent FANCD2 foci accumulation, which was suppressed by RNase H1 overexpression. In yeast, trabectedin and lurbinectedin increased the presence of Rad52 foci, a marker of DNA damage, in an R-loop–dependent manner. In addition to providing new insights into the mechanisms of action of these drugs, our study reveals that R-loops could be targeted by anticancer agents. Given the increasing evidence that R-loops occur all over the genome, the ability of lurbinectedin and trabectedin to act on them may contribute to enhance their efficacy, opening the possibility that R-loops might be a feature shared by specific cancers. The data presented in this study provide the new concept that R-loops are important cellular factors that contribute to trabectedin and lurbinectedin anticancer activity.

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