The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients

Malbec, L.; Celerier, M.; Bizet, M.; Calonne, E.; Hofmann-Winkler, H.; Boeckx, B.; Abdelnabi, R.; Putmans, P.; Hassabi, B.; Naesens, L.; Lambrechts, D.; Pöhlmann, S.; Deplus, R.; Delang, L.; Jeschke, J.; Fuks, F.

doi:10.1101/2022.06.27.497749

bioRxiv · 10.1101/2022.06.27.497749

The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients

Malbec, L.·Celerier, M.·Bizet, M.·Calonne, E.·Hofmann-Winkler, H.·Boeckx, B.·Abdelnabi, R.·Putmans, P.·Hassabi, B.·Naesens, L.·Lambrechts, D.·Pöhlmann, S.·Deplus, R.·Delang, L.·Jeschke, J.·Fuks, F.

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Abstract

The RNA modification N6-methyladenosine (m6A) plays a key role in the life cycles of several RNA viruses. Whether this applies to SARS-CoV-2 and whether m6A affects the outcome of COVID-19 disease is still poorly explored. Here we report that the RNA demethylase FTO strongly affects both m6A marking of SARS-CoV-2 and COVID-19 severity. By m6A profiling of SARS-CoV-2, we confirmed in infected cultured cells and showed for the first time in vivo in hamsters that the regions encoding TRS_L and the nucleocapsid protein are multiply marked by m6A, preferentially within RRACH motifs that are specific to {beta}-coronaviruses and well conserved across SARS-CoV-2 variants. In cells, downregulation of the m6A demethylase FTO, occurring upon SARS-CoV-2 infection, increased m6A marking of SARS-CoV-2 RNA and slightly promoted viral replication. In COVID-19 patients, a negative correlation was found between FTO expression and both SARS-CoV-2 expression and disease severity. FTO emerged as a classifier of disease severity and hence a potential stratifier of COVID-19 patients.

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Malbec, L., Celerier, M., Bizet, M., Calonne, E., Hofmann-Winkler, H., Boeckx, B., Abdelnabi, R., Putmans, P., Hassabi, B., Naesens, L., Lambrechts, D., Pöhlmann, S., Deplus, R., Delang, L., Jeschke, J., Fuks, F.. 2022-06-28. The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients. https://doi.org/10.1101/2022.06.27.497749

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