TY - JOUR
T1 - Nitric oxide inhibits FTO demethylase activity to regulate N6-methyladenosine mRNA methylation
AU - Kuschman, Hannah Petraitis
AU - Palczewski, Marianne B.
AU - Hoffman, Brian
AU - Menhart, Mary
AU - Wang, Xiaowei
AU - Glynn, Sharon
AU - Islam, Abul B.M.M.K.
AU - Benevolenskaya, Elizaveta V.
AU - Thomas, Douglas D.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85174461113
U2 - 10.1016/j.redox.2023.102928
DO - 10.1016/j.redox.2023.102928
M3 - Article
C2 - 37866163
AN - SCOPUS:85174461113
SN - 2213-2317
VL - 67
JO - Redox Biology
JF - Redox Biology
M1 - 102928
ER -
