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 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.