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. 2025 Jul 10;188(14):3728-3743.e20.
doi: 10.1016/j.cell.2025.04.020. Epub 2025 May 6.

m6A alters ribosome dynamics to initiate mRNA degradation

Shino Murakami  1 , Anthony O Olarerin-George  2 , Jianheng Fox Liu  1 , Sara Zaccara  3 , Ben Hawley  1 , Samie R Jaffrey  4
Affiliations

m6A alters ribosome dynamics to initiate mRNA degradation

Shino Murakami et al. Cell. .

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.

Keywords: N(6)-methyladenosine; TimeLapse-seq; adaptive response; amino acid depletion; m(6)A; mRNA decay; mRNA degradation; mRNA stability; ribosome collision; ribosome stall.

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Conflict of interest statement

Declaration of interests S.R.J. is the co-founder, advisor, and/or has equity in Chimerna Therapeutics, 858 Therapeutics, and Lucerna Technologies.

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