1. The anti-cancer drug 5-fluorouracil affects cell cycle regulators and potential regulatory long non-coding RNAs in yeast
- Author
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Maxime Wery, Ugo Szachnowski, Michael Primig, Emmanuelle Becker, Bingning Xie, Igor Stuparević, Antonin Morillon, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This study was supported by a PhD fellowship from La Ligue Contre le Cancer and La Région de Bretagne (ARED) to Bingning Xie, and a postdoctoral fellowship by La Région de Bretagne (SAD) to Igor Stuparevic. This work has also benefited from the facilities andexpertise of the NGS platform of Institut Curie, which are supported by the Agence Nationale de la Recherche (ANR-10-EQPX-03, ANR10-INBS-09-08), and the Canceropôle Ile-de-France. Further funding was provided by Inserm, the University of Rennes 1, and La LigueContre le Cancer to Michael Primig, and research grants from the Agence Nationale de la Recherche (REGULncRNA, DNA-Life), and the European Research Council (EpincRNA starting grant, DARK consolidator grant) to Antonin Morillon., ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU)
- Subjects
SWI5 ,Antimetabolites, Antineoplastic ,Saccharomyces cerevisiae Proteins ,Exosome complex ,Mitosis ,ACE2 ,Cell Cycle Proteins ,mitotic exit network ,5-fluorouracil ,transcription factor ,AMN1 ,long non-coding RNAs ,antisense RNA ,double stranded RNA ,chemotherapy ,yeast ,Saccharomyces cerevisiae ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Exoribonuclease ,RNA, Antisense ,RNA, Messenger ,Small nucleolar RNA ,Molecular Biology ,Gene ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Exosome Multienzyme Ribonuclease Complex ,Sequence Analysis, RNA ,Cell growth ,Cell Biology ,Cell cycle ,Antisense RNA ,Cell biology ,DNA-Binding Proteins ,Genes, cdc ,030220 oncology & carcinogenesis ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,RNA, Long Noncoding ,Fluorouracil ,Transcription Factors ,Research Paper - Abstract
International audience; 5-fluorouracil (5-FU) was isolated as an inhibitor of thymidylate synthase, which is important for DNA synthesis. The drug was later found to also affect the conserved 3'-5' exoribonuclease EXOSC10/Rrp6, a catalytic subunit of the RNA exosome that degrades and processes protein-coding and non-coding transcripts. Work on 5-FU's cytotoxicity has been focused on mRNAs and non-coding transcripts such as rRNAs, tRNAs and snoRNAs. However, the effect of 5-FU on long non-coding RNAs (lncRNAs), which include regulatory transcripts important for cell growth and differentiation, is poorly understood. RNA profiling of synchronized 5-FU treated yeast cells and protein assays reveal that the drug specifically inhibits a set of cell cycle regulated genes involved in mitotic division, by decreasing levels of the paralogous Swi5 and Ace2 transcriptional activators. We also observe widespread accumulation of different lncRNA types in treated cells, which are typically present at high levels in a strain lacking EXOSC10/Rrp6. 5-FU responsive lncRNAs include potential regulatory antisense transcripts that form double-stranded RNAs (dsRNAs) with overlapping sense mRNAs. Some of these transcripts encode proteins important for cell growth and division, such as the transcription factor Ace2, and the RNA exosome subunit EXOSC6/Mtr3. In addition to revealing a transcriptional effect of 5-FU action via DNA binding regulators involved in cell cycle progression, our results have implications for the function of putative regulatory lncRNAs in 5-FU mediated cytotoxicity. The data raise the intriguing possibility that the drug deregulates lncRNAs/dsRNAs involved in controlling eukaryotic cell division, thereby highlighting a new class of promising therapeutical targets.
- Published
- 2019
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