FTO, m6 Am , and the hypothesis of reversible epitranscriptomic mRNA modifications.

The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N6 -methyladenosine (m6 A). Although the pattern and distribution of m6 A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or 'erasers' allow m6 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 m6 A eraser, reveal that its physiologic target is not m6 A, but instead is N6 ,2'-O-dimethyladenosine (m6 Am ). Another m6 A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m6 A is generally not reversible, although m6 A may be susceptible to demethylation in pathophysiological states such as cancer.