Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation

Hannah Petraitis Kuschman, Marianne B. Palczewski, Brian Hoffman, Mary Menhart, Xiaowei Wang, Sharon Glynn, Abul B.M.M.K. Islam, Elizaveta V. Benevolenskaya, Douglas D. Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. Demethylation of m6A on mRNA is catalyzed by the enzyme fat mass and obesity-associated protein (FTO), a member of the nonheme Fe(II) and 2-oxoglutarate (2-OG)-dependent family of dioxygenases. FTO activity and m6A-mRNA are dysregulated in multiple diseases including cancers, yet endogenous signaling molecules that modulate FTO activity have not been identified. Here we show that nitric oxide (NO) is a potent inhibitor of FTO demethylase activity by directly binding to the catalytic iron center, which causes global m6A hypermethylation of mRNA in cells and results in gene-specific enrichment of m6A on mRNA of NO-regulated transcripts. Both cell culture and tumor xenograft models demonstrated that endogenous NO synthesis can regulate m6A-mRNA levels and transcriptional changes of m6A-associated genes. These results build a direct link between NO and m6A-mRNA regulation and reveal a novel signaling mechanism of NO as an endogenous regulator of the epitranscriptome.

Original languageEnglish (US)
Article number102928
JournalRedox Biology
Volume67
DOIs
StatePublished - Nov 2023

ASJC Scopus subject areas

  • Organic Chemistry

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