mA alters ribosome dynamics to initiate mRNA degradation.

Degradation of mRNA containing N-methyladenosine (mA) is essential for cell growth, differentiation, and stress responses. Here, we show that mA markedly alters ribosome dynamics and that these alterations mediate the degradation effect of mA on mRNA. We find that mA is a potent inducer of ribosome stalling, and these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts. We find that the degree of ribosome stalling correlates with mA-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced mA-mediated mRNA degradation. Ribosome stalling and collision at mA is followed by recruitment of YTHDF mA reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize mA-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial mA sensor for beginning mA-mRNA degradation.