Recognition of RNA N(6)-methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

N (6)-methyladenosine (m(6)A) 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 m(6)A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m(6)A)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 m(6)A-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 m(6)A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m(6)A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m(6)A readers in post-transcriptional gene regulation and cancer biology.