title: YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hailing
authors.initials: H
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhike
authors.initials: Z
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Boxuan S
authors.initials: BS
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Honghui
authors.initials: H
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.|Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D001483:Base Sequence; D003600:Cytosol / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism*; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D016601:RNA-Binding Proteins; C000600306:YTHDF1 protein, human; C585900:YTHDF2 protein, human; C000625021:YTHDF3 protein, human; D012313:RNA; C010223:N-methyladenosine; D000241:Adenosine