SUMMARY N6-methyladenosine (m6A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m6A-modified mRNA is regulated by an m6A reader protein, human YTHDF2, which recognizes m6A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that anotherm6A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m6A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m6A. Therefore, the m6A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.

N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

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