Recognition of RNA N-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.

N-methyladenosine (mA) 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 mA readers that target thousands of mRNA transcripts through recognizing the consensus GG(mA)C sequence. In contrast to the mRNA-decay-promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an mA-dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of mA and are critical for their oncogenic functions. Thus, our work reveals a different facet of the mA-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as mA readers in post-transcriptional gene regulation and cancer biology.