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Cell Res. 2017 Mar;27(3):315-328. doi: 10.1038/cr.2017.15. Epub 2017 Jan 20.

YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA.

Shi H1,2, Wang X1,2, Lu Z1,2, Zhao BS1,2, Ma H1,2, Hsu PJ1,2,3, Liu C1,2, He C1,2,4.

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Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.


N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, m6A binding protein YTHDF1 facilitates translation of m6A-modified mRNAs, and YTHDF2 accelerates the decay of m6A-modified transcripts. The biological function of YTHDF3, another cytoplasmic m6A binder of the YTH (YT521-B homology) domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of m6A-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of m6A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m6A RNA methylation.

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