Mechanisms and strategies for determining m⁶A RNA modification sites by natural and engineered m⁶A effector proteins

Abstract

N⁶-methyladenosine (m⁶A) is the most common internal RNA modification in the consensus sequence of 5′-RRACH-3′. The methyl mark is added by writer proteins (METTL3/METTL14 metyltransferase complex) and removed by eraser proteins (m⁶A demethylases; FTO and ALKBH5). Recognition of this methyl mark by m⁶A reader proteins leads to changes in RNA metabolism. How the writer and eraser proteins determine their targets is not well-understood, despite the importance of this information in understanding the regulatory mechanisms and physiological roles of m⁶A. However, approaches for targeted manipulation of the methylation state at specific sites are being developed. In this review, I summarize the recent findings on the mechanisms of target identification of m6A regulatory proteins, as well as recent approaches for targeted m⁶A modifications.