FTO, m⁶ 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 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 A_m ). 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.