Tumini, EmanuelaHerrera-Moyano, EmiliaSan Martín-Alonso, MartaBarroso, SoniaGalmarini, Carlos MAguilera, Andrés2023-01-252023-01-252018-12-14http://hdl.handle.net/10668/13311R-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. IMPLICATIONS: 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.enCarbolinesCell ProliferationDNA ReplicationGenomic InstabilityHeLa CellsHeterocyclic Compounds, 4 or More RingsHumansTrabectedinresearch article30552231open access10.1158/1541-7786.MCR-18-05751557-3125PMC6398590https://europepmc.org/articles/pmc6398590?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398590/pdf