Artículo
The antitumor drugs trabectedin and lurbinectedin induce transcription-dependent replication stress and genome instability
Autor/es | Tumini, Emanuela
Herrera Moyano, Emilia San Martín Alonso, Marta Barroso Ceballos, Sonia Inés Galmarini, Carlos María Aguilera López, Andrés |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2019 |
Fecha de depósito | 2020-10-02 |
Publicado en |
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Resumen | 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 ... 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. 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. |
Identificador del proyecto | ERC2014 AdG669898 TARLOOP
BFU2016-75058-P PRJ201402213 |
Cita | Tumini, E., Herrera Moyano, E., San Martín Alonso, M., Barroso Ceballos, S.I., Galmarini, C.M. y Aguilera López, A. (2019). The antitumor drugs trabectedin and lurbinectedin induce transcription-dependent replication stress and genome instability. The antitumor drugs trabectedin and lurbinectedin induce transcription-dependent replication stress and genome instability, 17 (3), 773-782. |
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