FTO , m6Am, 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 (m6A). Although the pattern and distribution of m6A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or ‘erasers’ allow m6A 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 m6A eraser, reveal that its physiologic target is not m6A, but instead is N6,2′‐O‐dimethyladenosine (m6Am). Another m6A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m6A is generally not reversible, although m6A may be susceptible to demethylation in pathophysiological states such as cancer.