m(6)A alters ribosome dynamics to initiate mRNA degradation.

Degradation of mRNA containing N(6)-methyladenosine (m(6)A) is essential for cell growth, differentiation, and stress responses. Here, we show that m(6)A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m(6)A on mRNA. We find that m(6)A 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 m(6)A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m(6)A-mediated mRNA degradation. Ribosome stalling and collision at m(6)A is followed by recruitment of YTHDF m(6)A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m(6)A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m(6)A sensor for beginning m(6)A-mRNA degradation.