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

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

Huilin Huang ¹ ², Hengyou Weng ¹ ², Wenju Sun ³ ⁴, Xi Qin ¹ ², Hailing Shi ⁵ ⁶, Huizhe Wu ¹ ² ⁷, Boxuan Simen Zhao ⁵ ⁶, Ana Mesquita ¹, Chang Liu ⁵ ⁶, Celvie L Yuan ⁸, Yueh-Chiang Hu ⁸, Stefan Hüttelmaier ⁹, Jennifer R Skibbe ¹, Rui Su ¹ ², Xiaolan Deng ¹ ² ⁷, Lei Dong ¹ ², Miao Sun ¹⁰, Chenying Li ¹ ² ¹¹, Sigrid Nachtergaele ⁵ ⁶, Yungui Wang ¹ ¹¹, Chao Hu ¹ ¹¹, Kyle Ferchen ¹, Kenneth D Greis ¹, Xi Jiang ¹ ², Minjie Wei ⁷, Lianghu Qu ³ ⁴, Jun-Lin Guan ¹, Chuan He ¹² ¹³, Jianhua Yang ¹⁴ ¹⁵, Jianjun Chen ¹⁶ ¹⁷

Affiliations

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.

PMID: 29476152 DOI: 10.1038/s41556-018-0045-z

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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