Cytosine-5 RNA methylation links protein synthesis to cell metabolism

by Nikoletta A. Gkatza, Cecilia Castro, Robert F. Harvey, Matthias Hei ß, Martyna C. Popis, Sandra Blanco, Susanne Bornelöv, Abdulrahim A. Sajini, Joseph G. Gleeson, Julian L. Griffin, James A. West, Stefanie Kellner, Anne E. Willis, Sabine Dietmann, Michaela Frye

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 pathwa ys 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 tR NA 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 correl ated 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 pr...

Source: PLoS Biology: Archived Table of Contents - June 13, 2019 Category: Biology Authors: Nikoletta A. Gkatza Source Type: research