Recognition of RNA N6-methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

By Huilin Huang, Hengyou Weng, Wenju Sun, Xi Qin, Hailing Shi, Huizhe Wu, B. Zhao, Ana Mesquita, Chang Liu, Celvie L. Yuan and 20 more. Nature Cell Biology, 2018

2,518 citations recorded by the source corpus.

N6-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 YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an m6A-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 m6A and are critical for their oncogenic functions. Thus, our work 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. Huang et al. identify IGF2BPs as an additional class of N6-methyladenosine (m6A) reader proteins. They find that IGF2BPs selectively bind to m6A-containing mRNAs and promote their stability.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/80b13419ae0c6fba51131542f2d76be9b2ee5bbb

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In Molecular Biology

1. Chuan He
2. P. He
3. Syuzo Kaneko
4. Masaaki Komatsu
5. Ken Asada
6. Ken Takasawa
7. Hailing Shi
8. Jiangbo W

Citations in the corpus

• The role of m6A RNA methylation in cancer metabolism (2022, background): “The most famous m6A readers are YTHDF family and IGF2BP family [27].”
• YTH Domain: A Family of N6-methyladenosine (m6A) Readers (2018, background): “Besides the YTH family proteins, other RNA-binding proteins (RBPs), such as heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) [49], embryonic lethal, abnormal vision-like protein 1 (ELAVL1) [50], and insulin-like growth factor 2 mRNA-binding proteins 1–3 (IGF2BP1–3) [51], are also suggested”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “Recently, IGF2BP1, IGF2BP2, and IGF2BP3 were reported to bind m 6 A-methylated transcripts and stabilize them (Huang et al , 2018).”
• RNA modifications modulate gene expression during development (2018, positive): “The list of m 6 A readers regulating mRNA homeostasis is still growing ( 11, 12 ), and the functions of m 6 A could depend on recognition by cell type-specific reader proteins.”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “IGF2BPs enhance expression of target mRNA by promoting the stability of target mRNA through binding to mRNA stabilizers like ELAVL1 and MATR3 under normal conditions and by promoting the storage of target mRNA through translocating to stress granules under stress condition [26].”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “In addition, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs, including IGF2BP1/2/3) can identify m6A and promote mRNA stability and translation in an m6Adependent manner [40].”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “m6A readers IGF2BPs have also been reported to promote the stability and expression of their target mRNAs, including MYC, by regulating m6A abundance [43].”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “IGF2BP1–3 and YTHDF2, which regulate mRNA stability in opposite directions, were shown to bind distinct sites on mRNA: the former favors 3’UTR in HEK293T cells examined while the latter shows more binding to CDS (Huang et al., 2018).”
• RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “MYC is a critical target of IGF2BPs in cancers, and its depletion mimics the phenotypes caused by IGF2BP depletion while its overexpression can rescue the effects of IGF2BP depletion.(25) Collectively, IGF2BPs elicit oncogenic functions as m(6)A readers in promoting proliferation, migration, and inv”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “In the aspect of mRNA stability control, earlier studies generally considered m(6)A as a destabilizer facilitating mRNA degradation mainly through YTHDF2,(20,21,52,55) while a recent study revealed a distinct function of m(6)A mediated by IGF2BP proteins in promoting the stability and storage of the”