YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs

• DOI: 10.7554/elife.31311
• Publication Date: 2017-10-06T12:00:12Z
• Authors: Ian A Roundtree; Guan-Zheng Luo; Zijie Zhang; Xiao Wang; Tao Zhou; Yiquang Cui; Jiahao Sha; Xingxu Huang; Laura Guerrero; Phil Xie; Emily He; Bin Shen; Chuan He
• Keywords: 0301 basic medicine; Nucleocytoplasmic Transport Proteins; Adenosine; QH301-705.5; Science; Active Transport, Cell Nucleus; 610; Nerve Tissue Proteins; 03 medical and health sciences; Biochemistry and Chemical Biology; Humans; RNA, Messenger; Biology (General); mRNA export; 0303 health sciences; Serine-Arginine Splicing Factors; Q; R; RNA-Binding Proteins; RNA modification; RNA processing; Gene Knockdown Techniques; Medicine; RNA Splicing Factors; gene regulation; HeLa Cells; Protein Binding

N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic messenger RNA (mRNA) and plays critical roles in RNA biology. The function of this modification is mediated by m6A-selective ‘reader’ proteins of the YTH family, which incorporate m6A-modified mRNAs into pathways of RNA metabolism. Here, we show that the m6A-binding protein YTHDC1 mediates export of methylated mRNA from the nucleus to the cytoplasm in HeLa cells. Knockdown of YTHDC1 results in an extended residence time for nuclear m6A-containing mRNA, with an accumulation of transcripts in the nucleus and accompanying depletion within the cytoplasm. YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, and facilitates RNA binding to both SRSF3 and NXF1. This role for YTHDC1 expands the potential utility of chemical modification of mRNA, and supports an emerging paradigm of m6A as a distinct biochemical entity for selective processing and metabolism of mammalian mRNAs.