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

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          Abstract

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

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          Most cited references26

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          m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.

          N(6)-methyladenosine (m(6)A) has been recently identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, but its features, regulatory mechanisms, and functions in cell reprogramming are largely unknown. Here, we report m(6)A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several features of m(6)A, especially gene- and cell-type-specific m(6)A mRNA modifications. We also show that microRNAs (miRNAs) regulate m(6)A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m(6)A modification levels through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m(6)A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs) to pluripotent stem cells; conversely, reduced m(6)A levels impede reprogramming. Our results therefore uncover a role for miRNAs in regulating m(6)A formation of mRNAs and provide a foundation for future functional studies of m(6)A modification in cell reprogramming.
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            Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies.

            Eukaryotic cells contain nontranslating messenger RNA concentrated in P-bodies, which are sites where the mRNA can be decapped and degraded. We present evidence that mRNA molecules within yeast P-bodies can also return to translation. First, inhibiting delivery of new mRNAs to P-bodies leads to their disassembly independent of mRNA decay. Second, P-bodies decline in a translation initiation-dependent manner during stress recovery. Third, reporter mRNAs concentrate in P-bodies when translation initiation is blocked and resume translation and exit P-bodies when translation is restored. Fourth, stationary phase yeast have large P-bodies containing mRNAs that reenter translation when growth resumes. The reciprocal movement of mRNAs between polysomes and P-bodies is likely to be important in the control of mRNA translation and degradation. Moreover, the presence of related proteins in P-bodies and maternal mRNA storage granules suggests this mechanism is widely adapted for mRNA storage.
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              A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development.

              Insulin-like growth factor II (IGF-II) is a major fetal growth factor. The IGF-II gene generates multiple mRNAs with different 5' untranslated regions (5' UTRs) that are translated in a differential manner during development. We have identified a human family of three IGF-II mRNA-binding proteins (IMPs) that exhibit multiple attachments to the 5' UTR from the translationally regulated IGF-II leader 3 mRNA but are unable to bind to the 5' UTR from the constitutively translated IGF-II leader 4 mRNA. IMPs contain the unique combination of two RNA recognition motifs and four hnRNP K homology domains and are homologous to the Xenopus Vera and chicken zipcode-binding proteins. IMP localizes to subcytoplasmic domains in a growth-dependent and cell-specific manner and causes a dose-dependent translational repression of IGF-II leader 3 -luciferase mRNA. Mouse IMPs are produced in a burst at embryonic day 12.5 followed by a decline towards birth, and, similar to IGF-II, IMPs are especially expressed in developing epithelia, muscle, and placenta in both mouse and human embryos. The results imply that cytoplasmic 5' UTR-binding proteins control IGF-II biosynthesis during late mammalian development.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                28 January 2018
                23 February 2018
                March 2018
                23 August 2018
                : 20
                : 3
                : 285-295
                Affiliations
                [1 ]Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45219, USA
                [2 ]Department of Systems Biology, City of Hope, Monrovia, CA 91016, USA
                [3 ]Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
                [4 ]State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
                [5 ]Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA
                [6 ]Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
                [7 ]Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA
                [8 ]Institute of Molecular Medicine, Department of Molecular Cell Biology, Martin-Luther-University, Heinrich-Damerow-Str.1, 06120 Halle, Germany
                [9 ]Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA
                [10 ]Key Laboratory of Hematopoietic Malignancies; Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China
                Author notes
                [12 ]Correspondence should be addressed to J.C., J.Y., or C.H. ( jianchen@ 123456coh.org ; yangjh7@ 123456mail.sysu.edu.cn ; or chuanhe@ 123456uchicago.edu )
                [11]

                These authors contributed equally to this work.

                Article
                NIHMS937118
                10.1038/s41556-018-0045-z
                5826585
                29476152
                623178bf-06a3-416a-9374-5426b12d8dac

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                Article

                Cell biology
                igf2bp,rna n6-methyladenosine,readers,mrna stability,translation,k homology domain,myc
                Cell biology
                igf2bp, rna n6-methyladenosine, readers, mrna stability, translation, k homology domain, myc

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