FTO

Nuclear, Fe(II)- and 2-oxoglutarate-dependent oxygenase of the AlkB superfamily that oxidizes methyl groups on single-stranded nucleic acids. Its AlkB-like catalytic domain is paired with a C-terminal domain of novel fold, and an active-site loop excludes duplex substrates, so FTO acts only on single-stranded DNA and RNA. The best-supported cellular substrates are methylated adenosines in small RNAs and mRNA: N6,2'-O-dimethyladenosine (m6Am) at the transcription-start nucleotide of snRNAs and of capped mRNAs, N6-methyladenosine in U6 snRNA, and N1-methyladenosine in tRNA, the last of which represses translation. FTO can also oxidize internal N6-methyladenosine in mRNA and, in vitro, repair-type lesions such as 3-methylthymine in ssDNA and 3-methyluracil in ssRNA. Two aspects of its activity are actively disputed. Chemically, isolated FTO appears to stop at the hemiaminal N6-hydroxymethyladenosine rather than releasing formaldehyde itself, so demethylation may complete non-enzymatically, unlike the related ALKBH5 and AlkB enzymes. Biologically, whether internal mRNA m6A is a physiological substrate is contested: antibody-based transcriptome mapping supports it, while quantitative direct-RNA sequencing finds no change in mRNA m6A stoichiometry on FTO loss, with snRNA m6Am rising instead. FTO is mainly nuclear, concentrating in nuclear speckles, with a cell-type-dependent cytoplasmic pool. Complete loss of catalytic activity causes a lethal recessive polymalformation syndrome in humans, and the protein is widely studied as a candidate target in acute myeloid leukemia. Common variants in FTO intron 1 give the strongest known common-variant association with body mass index, but that association acts largely by altering enhancer-driven expression of the distant IRX3 and IRX5 genes rather than by altering FTO protein function.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.