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 (m⁶A_m). 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. [ABSTRACT FROM AUTHOR]