Understanding the redundant functions of the m⁶A-binding YTHDF proteins

Abstract

N6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA and it has important functions in mRNA regulation. However, our understanding of the specific functions of m6A along with its cytosolic readers, the YTHDF proteins, has changed substantially in recent years. The original view was that different m6A sites within an mRNA could have different functions depending on which YTHDF paralog was bound to it, with bound YTHDF1 inducing translation while bound YTHDF2 inducing mRNA degradation. More recent data has called much of this into question, showing that all m6A sites bind all YTHDF proteins with equal ability, with a single primary function of all three YTHDF proteins to mediate mRNA degradation. Here we describe the diverse technical concerns that led to the original model being questioned, the newer data that overturned this model and led to the new understanding of m6A and YTHDF function, and how any remaining questions about the functions of the YTHDF proteins can be readily resolved.

RNA Binding by the m6A Methyltransferases METTL16 and METTL3

“…Thus, it does appear that, depending on the m6A reader that recognizes the mRNA, modification can have a multitude of effects. However, more recent studies suggest that mRNA degradation is the major effect of m6A modification, especially with regard to recognition by the TYHDF reader proteins, which appear to be redundant in function [ 91 ]. Whether this is true of other reader proteins and/or protein families will require more careful analysis of the data.…”