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5-Fluorouracil affects assembly of stress granules based on RNA incorporation

MPG-Autoren
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Kähler,  Christian
Neurodegenerative Disorders (Sylvia Krobitsch), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Isensee,  Jörg
Signal Transduction in Mental Retardation and Pain (Tim Hucho), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hucho,  Tim
Signal Transduction in Mental Retardation and Pain (Tim Hucho), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Lehrach,  Hans
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Krobitsch,  Sylvia
Neurodegenerative Disorders (Sylvia Krobitsch), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

Externe Ressourcen

http://www.ncbi.nlm.nih.gov/pubmed/24728989
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Kaehler.pdf
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Zitation

Kähler, C., Isensee, J., Hucho, T., Lehrach, H., & Krobitsch, S. (2014). 5-Fluorouracil affects assembly of stress granules based on RNA incorporation. Nucleic Acids Research (London), 42(10), 6436-6447. doi:10.1093/nar/gku264.


Zitierlink: https://hdl.handle.net/11858/00-001M-0000-0025-7808-E
Zusammenfassung
The antimetabolite 5-fluorouracil is a widely used chemotherapeutic for the treatment of several solid cancers. However, resistance to 5-fluorouracil remains a major drawback in its clinical use. In this study we report that treatment of HeLa cells with 5-fluorouracil resulted in de novo assembly of stress granules. Moreover, we revealed that stress granule assembly under stress conditions as well as disassembly is altered in cells treated with 5-fluorouracil. Notably, we discovered that RACK1, a protein mediating cell survival and apoptosis, is a component of 5-fluorouracil-induced stress granules. To explore the mode of action of 5-fluorouracil accountable for de novo stress granule assembly, we analyzed 5-fluorouracil metabolites and noticed that stress granule assembly is caused by RNA, not DNA incorporating 5-fluorouracil metabolites. Interestingly, we observed that other RNA incorporating drugs also cause assembly of stress granules. Thus, our results suggest that incorporation of chemotherapeutics into RNA may result in stress granule assembly with potential significance in chemoresistance.