Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase

By X. Ping, Bao-Fa Sun, Lu Wang, Wen Xiao, Xin Yang, Wen-Jia Wang, Samir Adhikari, Yue Shi, Ying Lv, Yu-Sheng Chen and 15 more. Cell Research, 2014

2,093 citations recorded by the source corpus.

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 activity 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-enhanced 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/522c65882ed4f9ade392f0f22cab973de0662591

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In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. P. He
4. Kate D. Meyer
5. Hailing Shi
6. Jiangbo W
7. Syuzo Kaneko
8. Masaaki Komatsu

Citations in the corpus

• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Wilms tumor 1-associating protein (WTAP) binds to METTL3/14 and is required for optimal substrate recruitment and METTL3/14 localization (Ping et al., 2014; Zhong et al., 2008); Vir like m6A methyltransferase associated (VIRMA) is critical for deposition of m6A specifically to the 3’UTR (Yue et al.”
• Methylation multiplicity and its clinical values in cancer (2021, neutral): “23).”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “Wilms Tumor 1 associated protein (WTAP) ensures the localization of the METTL3-METTL14 heterodimer to the nuclear speckle and promotes catalytic activity [16, 19].”
• The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells (2017, neutral): “This likely reflects stabilization of METTL14 by binding METTL3 as described previously 26 .”
• Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, background): “Previous studies suggest that m6A methylation takes place within the nucleus, probably in the nuclear speckles (Ping et al., 2014).”
• METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.”
• N 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein (2017, methodology): “m6A is a reversible and dynamic modification that is introduced at a subset of RRACH motifs (R = A/G, H = A/C/U) through the activity of the m6A methyltransferase complex, composed of methyltransferase-like 3 (METTL3), METTL14 and Wilms tumor 1 associated protein (2,3), and reversed by two m6A demet”
• Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases (2016, neutral): “For normal m(6)Amodification to occur in cells, Mettl3 andMettl14 also need to associate with additional factors that may aid with proper localization, such as Wilm’s tumor 1-associated protein (WTAP) (Ping et al., 2014; Schwartz et al., 2014).”