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页码: 177-189
被引频次: 365
出版者: INST BIOCHEMISTRY & CELL BIOLOGY,Nature Publishing Group
ISSN: 1001-0602
卷期: Volume:24    Issue:2
语言: English
摘要: The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
相关主题: 选择性剪接, 复合物, RNA加工, 亚基, mRNA, 相关蛋白, 哺乳动物, 肾母细胞瘤, METTL14, WTAP, m6A methyltransferase, METTL3, PAR-CLIP, LARGE GENE LISTS, BINDING PROTEIN, N-6-ADENOSINE METHYLATION, SACCHAROMYCES-CEREVISIAE, PRE-MESSENGER-RNA, CELL BIOLOGY, IN-VITRO, HETEROGENEOUS NUCLEAR-RNA, PARTIAL-PURIFICATION, REVEALS, Alternative Splicing, Humans, Methyltransferases - metabolism, Embryo, Nonmammalian - metabolism, Gene Expression Regulation, Methyltransferases - genetics, Nuclear Proteins - metabolism, Gene Expression Profiling, RNA, Messenger - metabolism, Zebrafish - growth & development, Animals, Cell Nucleus - metabolism, Methyltransferases - antagonists & inhibitors, RNA Interference, Nuclear Proteins - antagonists & inhibitors, HEK293 Cells, Protein Binding, Cell Differentiation, HeLa Cells, Nuclear Proteins - genetics, RNA, Small Interfering - metabolism, Original,

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