The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate–Dependent Nucleic Acid Demethylase
By T. Gerken, C. Girard, Y. C. Tung, Celia J. Webby, V. Saudek, K. Hewitson, G. Yeo, M. McDonough, S. Cunliffe, Luke A. McNeill and 15 more. Science, 2007
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Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate–dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/4b537a6953d4726ddd6ced4fe1ef4ca96296b597
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In Molecular Biology
Citations in the corpus
- N6-methyl-adenosine (m6A) in RNA: An Old Modification with A Novel Epigenetic Function (2012, background): “FTO and ALKBH5 belong to the AlkB family owing to the conserved iron binding motif and a-ketoglutarate interaction domain [51–54] (Figure 1; Figure 2B).”
- Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. (2008, background): “The cupin protein superfamily comprises several other enzymes that could potentially function as histone demethylases, including the recently characterized fat mass and obesity-associated (FTO) gene (Gerken et al. 2007) and the previously identified AlkbH enzymes (Falnes et al.”
- Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3' UTRs and Near Stop Codons (2012, neutral): “FTO is a member of the Fe(II)and oxoglutarate-dependent AlkB oxygenase family and was originally shown to catalyze the oxidative demethylation of methylated thymidine and uracil (Gerken et al., 2007; Jia et al., 2008).”
- Mechanisms of DNA damage, repair and mutagenesis (2017, neutral): “ALKBH1-8 (Alkylation Repair Homologs) and FTO (Fat Mass and Obesity associated) in human cells [Kurowski et al., 2003; Gerken et al., 2007; Sanchez-Pulido and Andrade-Navarro, 2007; Yi and He, 2013].”
- Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5 (2014, background): “FTO belongs to the family of Fe2+ and 2-oxoglutarate (2OG) dependent AlkB dioxygenases (12) and contributes to non-syndromic human obesity (13).”
- YTH Domain: A Family of N6-methyladenosine (m6A) Readers (2018, background): “FTO and ALKBH5 are the only two known m(6)A demethylases found in humans and they both belong to the a-ketoglutarate-dependent dioxygenase family [23,26].”
- ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility (2012, positive): “Indeed, we discovered that the human obesity-associated FTO protein (Fischer et al., 2009; Frayling et al., 2007; Gerken et al., 2007; Scott et al., 2007) is an RNA demethylase that oxidatively removes the m(6)A modification in mRNA (Jia et al.”