A birds'‐eye view of the activity and specificity of the mRNA m6A methyltransferase complex

Advanced Review

David Garcias Morales, José L. Reyes

Published Online: Jul 20 2020

DOI: 10.1002/wrna.1618

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Abstract Appropriate control of the transcriptome is essential to regulate different aspects of gene expression during development and in response to environmental stimuli. Fast accumulating reports are recognizing and functionally characterizing several types of modifications across transcripts, which have created a new field of RNA study named epitranscriptomics. The most abundant modification found in messenger RNA (mRNA) is N6‐methyladenosine (m6A). m6A addition is achieved by a large methyltransferase complex (MTC). The m6A‐MTC is composed of the methyltransferases METTL3 and METTL14 as the catalytic core, and several protein factors necessary for its correct catalysis, which include WTAP, RBM15, VIRMA, HAKAI, and ZC3H13. To fully appreciate the relevance of this modification, it is important to dissect the basis for the MTC function as well as to define its interaction with other cellular partners. Here, we summarize previous and recent knowledge on these issues to provide a guide for future research and put forward ideas on the flexibility and specificity of this process. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition

The process of m⁶A modification of messenger RNA (mRNA) in eukaryotic cells. The addition of a methyl group to selected adenosines in mRNAs occurs in a cotranscriptional manner [indicated as 1 in the figure], as the methyltransferase complex (MTC), comprised of the essential factors METTL3, METTL14, and WTAP interacts with the RNA polymerase II (RNAP II) complex. The process can be reversed by a demethylase enzyme of the FTO or ALKBH5 family [2]. Alternatively, the m⁶A‐modified transcript is bound by a protein factor of the YTH family; also, it can be exported to the cytoplasm where it is recognized by a protein factor, mainly of the YTH family [3]. This interaction can then funnel the m⁶A‐modified transcript to one of two main outcomes, increased translation [4] by interaction with ribosomal components, or it can be channeled to degradation [5], by interaction with P‐body components. Thus, m⁶A influences the functionality of modified transcripts to regulate gene expression at the post‐transcriptional level

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The methyltransferase complex: The components and their interactions. m⁶Aaddition is a co‐transcriptional process, where the MTC is constantly catalyzing this reaction. The METTL3/METTL14 heterodimer forms in the cytoplasm andthen it is recruited into the nucleus by means of the NLS present in METTL3. Inthe nucleus, METTL3 can interact through its Leader Helix regions with the coiled‐coil portion of WTAP. WTAP also interacts with ZC3H13 to retain the MTC inside the nucleus, in turn, ZC3H13 can interact with RBM15. The main role of RBM15 in m⁶A addition is to recruit the MTC to U‐rich sequences immediately adjacent to RRACH motifs. Another protein that also interacts with WTAP is VIRMA, which is involved in providing sequence specificity and recruitment of the MTC to guide methylation in 3’UTR regions and near stop codons. The last protein of the MTC described to date is HAKAI but how its E3‐ubiquitin ligase function contributes to m⁶A addition is unclear

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Catalytic core of the METTL3/METTL14 heterodimer. METTL3 and METTL14 interact with each other via their methyltransferase domains (MTD) to form a fuctional heterodimer. Within the MTD of METTL3 the [3H]–S‐adenosylmethionine (SAM)‐binding site is formed by a partially disordered loop named Active Site Loop 1 (ASL1) and a fully ordered named Active Site Loop 2 (ASL2). A conserved DPPW motif in loop 1 is involved in coordinating the adenine group of the acceptor RNA substrate. In contrast, the putative catalytic cavity of METTL14 (EPPL motif) adopts a closed conformation. The two zinc fingers in METTL3 ZFD1/ZFD2 are responsible for the complex's specificity for the RRACH motif, while the METTL14 RGG repeats allow mRNA binding in a sequence‐independent manner

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