Cytosine-5 RNA methylation links protein synthesis to cell metabolism

PLoS Biol. 2019 Jun 14;17(6):e3000297. doi: 10.1371/journal.pbio.3000297.

Nikoletta A Gkatza ¹, Cecilia Castro ², Robert F Harvey ³, Matthias Heiß ⁴, Martyna C Popis ¹, Sandra Blanco ⁵ ⁶, Susanne Bornelöv ⁷, Abdulrahim A Sajini ⁸, Joseph G Gleeson ⁹, Julian L Griffin ², James A West ², Stefanie Kellner ⁴, Anne E Willis ³, Sabine Dietmann ⁷, Michaela Frye ¹ ¹⁰

Affiliations

1 Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
2 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
3 Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.
4 Department of Chemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
5 Cancer Cell Signaling and Metabolism Lab, Proteomics Unit CIC bioGUNE, Derio, Spain.
6 Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, Salamanca, Spain.
7 Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
8 Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
9 Department of Neurosciences, San Diego School of Medicine, University of California, La Jolla, California, United States of America.
10 German Cancer Center (Deutsches Krebsforschungszntrum), Heidelberg, Germany.

PMID: 31199786 DOI: 10.1371/journal.pbio.3000297

Abstract

Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.

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