FTO, m 6 A m , and the hypothesis of reversible epitranscriptomic mRNA modifications.

The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N ⁶ -methyladenosine (m ⁶ A). Although the pattern and distribution of m ⁶ A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or 'erasers' allow m ⁶ A to be dynamically reversed by signaling pathways. In this Review, we discuss the data in support and against this model. New insights into the function of fat mass and obesity-associated protein (FTO), the original enzyme thought to be an m ⁶ A eraser, reveal that its physiologic target is not m ⁶ A, but instead is N ⁶ ,2'-O-dimethyladenosine (m ⁶ A _m ). Another m ⁶ A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m ⁶ A is generally not reversible, although m ⁶ A may be susceptible to demethylation in pathophysiological states such as cancer.
(© 2018 Federation of European Biochemical Societies.)