m⁶A alters ribosome dynamics to initiate mRNA degradation.

Abstract

Degradation of mRNA containing N⁶-methyladenosine (m⁶A) is essential for cell growth, differentiation, and stress responses. Here, we show that m⁶A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m⁶A on mRNA. We find that m⁶A 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 m⁶A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m⁶A-mediated mRNA degradation. Ribosome stalling and collision at m⁶A is followed by recruitment of YTHDF m⁶A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m⁶A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m⁶A sensor for beginning m⁶A-mRNA degradation.