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Nat Cell Biol. 2018 Mar;20(3):285-295. doi: 10.1038/s41556-018-0045-z. Epub 2018 Feb 23.

Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.

Huang H1,2, Weng H1,2, Sun W3,4, Qin X1,2, Shi H5,6, Wu H1,2,7, Zhao BS5,6, Mesquita A1, Liu C5,6, Yuan CL8, Hu YC8, Hüttelmaier S9, Skibbe JR1, Su R1,2, Deng X1,2,7, Dong L1,2, Sun M10, Li C1,2,11, Nachtergaele S5,6, Wang Y1,11, Hu C1,11, Ferchen K1, Greis KD1, Jiang X1,2, Wei M7, Qu L3,4, Guan JL1, He C12,13, Yang J14,15, Chen J16,17.

Author information

1
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
2
Department of Systems Biology, City of Hope, Monrovia, CA, USA.
3
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, China.
4
State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
5
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.
6
Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
7
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.
8
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
9
Institute of Molecular Medicine, Department of Molecular Cell Biology, Martin Luther University, Halle, Germany.
10
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
11
Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
12
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
13
Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
14
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, China. yangjh7@mail.sysu.edu.cn.
15
State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China. yangjh7@mail.sysu.edu.cn.
16
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. jianchen@coh.org.
17
Department of Systems Biology, City of Hope, Monrovia, CA, USA. jianchen@coh.org.

Abstract

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.

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PMID:
29476152
PMCID:
PMC5826585
DOI:
10.1038/s41556-018-0045-z
[Indexed for MEDLINE]
Free PMC Article

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