Figure 4. The effects of N⁶-methyladenosine on mRNA translation and decay.

a | ‘Writer’ proteins establish N⁶-methyladenosine (m⁶A) at internal RNA sites, ‘eraser’ proteins remove them, and ‘reader’ proteins directly bind the N⁶-methyl group of m⁶A (reviewed in REF. 148). The listed readers affect the translation and stability of m⁶A-modified mRNAs. b | m⁶A modifications in mRNAs occur with a preference for the last exon and 3′ untranslated region (UTR)²⁰¹ and are increased during stress¹⁵². According to its position in the mRNA, m⁶A is bound by readers that can induce cap-dependent translation or internal ribosome recruitment. In the 5′ UTR, eukaryotic initiation factor 3 (eIF3) can directly bind m⁶A and facilitate internal translation initiation¹⁵¹. Stress-responsive 5′ UTR N⁶-adenosine methylation, for example during heat shock, is preserved by YTH domain-containing family protein 2 (YTHDF2), which blocks binding of the eraser fat mass and obesity-associated protein (FTO), thereby promoting cap-independent translation initiation of stress response mRNAs¹⁵². m⁶A in the coding sequence (CDS) is linked to tRNA selection¹⁶³, and at the 3′ UTR it is linked to increased translation owing to YTHDF1 binding to m⁶A and eIF3 recruitment for cap-dependent translation¹⁵⁸. The writer methyltransferase like 3 protein (METTL3) can also directly bind to eIF3 to increase translation of m⁶A-containing mRNAs independently of its m⁶A writer activity¹⁵⁹. By contrast, YTHDF2 promotes degradation of m⁶A-modified mRNAs by recruiting the deadenylase complex CCR4–NOT¹⁵⁷. Together, increased translation efficiency and activated decay of m⁶A-modified mRNAs allow dynamic regulation of protein synthesis. c | m⁶A mRNA modifications are associated with unfolded RNA structures. N⁶ adenosine methylation in a stem disrupts based paired regions (‘m⁶A switch’), which allows binding of the ‘indirect reader’ heterogeneous nuclear ribonucleoprotein C (hnRNPC) to exposed U rich motifs in the nucleus¹⁵³. CNOT1, CCR4–NOT transcription complex subunit 1; HSP70, heat shock protein 70; P body, processing body. Part c is adapted from REF. 153, Macmillan Publishers Limited.