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 19 2020

DOI: 10.1002/wrna.1618

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

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

[ Normal View | Magnified View ]

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

[ Normal View | Magnified View ]

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

[ Normal View | Magnified View ]

References

Agarwala,, S. D., Blitzblau,, H. G., Hochwagen,, A., & Fink,, G. R. (2012). RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genetics, 8(6), e1002732.
Aguilo,, F., Zhang,, F., Sancho,, A., Fidalgo,, M., Di Cecilia,, S., Vashisht,, A., … Walsh,, M. J. (2015). Coordination of m6A mRNA methylation and gene transcription by ZFP217 regulates pluripotency and reprogramming. Cell Stem Cell, 17(6), 689–704.
Akichika,, S., Hirano,, S., Shichino,, Y., Suzuki,, T., Nishimasu,, H., Ishitani,, R., … Suzuki,, T. (2019). Cap‐specific terminal N⁶−methylation of RNA by an RNA polymerase II–associated methyltransferase. Science, 363(6423), eaav0080.
Alarcon,, C. R., Lee,, H., Goodarzi,, H., Halberg,, N., & Tavazoie,, S. F. (2015). N6‐methyladenosine marks primary microRNAs for processing [Letter]. Nature, 519(7544), 482–485.
An,, S., Huang,, W., Huang,, X., Cun,, Y., Cheng,, W., Sun,, X., … Wang,, J. (2020). Integrative network analysis identifies cell‐specific trans regulators of m6A. Nucleic Acids Research, 48, 1715–1729.
Balacco,, D. L., & Soller,, M. (2019). The m6A writer: Rise of a machine for growing tasks. Biochemistry, 58(5), 363–378.
Beemon,, K., & Keith,, J. (1977). Localization of N6‐methyladenosine in the Rous sarcoma virus genome. Journal of Molecular Biology, 113(1), 165–179.
Bevilacqua,, P. C., Ritchey,, L. E., Su,, Z., & Assmann,, S. M. (2016). Genome‐wide analysis of RNA secondary structure. Annual Review of Genetics, 50(1), 235–266.
Bhat,, S. S., Bielewicz,, D., Grzelak,, N., Gulanicz,, T., Bodi,, Z., Szewc,, L., … Szweykowska‐Kulinska,, Z. (2019). mRNA adenosine methylase (MTA) deposits m⁶A on pri‐miRNAs to modulate miRNA biogenesis in Arabidopsis thaliana. bioRxiv, 557900.
Bodi,, Z., Button,, J. D., Grierson,, D., & Fray,, R. G. (2010). Yeast targets for mRNA methylation. Nucleic Acids Research, 38(16), 5327–5335.
Bodi,, Z., Zhong,, S., Mehra,, S., Song,, J., Graham,, N., Li,, H., … Fray,, R. G. (2012). Adenosine methylation in arabidopsis mRNA is associated with the 3′ end and reduced levels cause developmental defects. Frontiers in Plant Science, 3, 48.
Bokar,, J. A., Rath‐Shambaugh,, M. E., Ludwiczak,, R., Narayan,, P., & Rottman,, F. (1994). Characterization and partial purification of mRNA N6‐adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. Journal of Biological Chemistry, 269(26), 17697–17704.
Bokar,, J. A., Shambaugh,, M. E., Polayes,, D., Matera,, A. G., & Rottman,, F. M. (1997). Purification and cDNA cloning of the AdoMet‐binding subunit of the human mRNA (N6‐adenosine)‐methyltransferase. RNA, 3(11), 1233–1247.
Bujnicki,, J. M., Feder,, M., Radlinska,, M., & Blumenthal,, R. M. (2002). Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT‐A70 subunit of the human mRNA:m6A Methyltransferase. Journal of Molecular Evolution, 55(4), 431–444.
Canaani,, D., Kahana,, C., Lavi,, S., & Groner,, Y. (1979). Identification and mapping of N 6 ‐methyladenosine containing sequences in Simian virus 40 RNA. Nucleic Acids Research, 6(8), 2879–2899.
Canaani,, E., Robbins,, K. C., & Aaronson,, S. A. (1979). The transforming gene of Moloney murine sarcoma virus. Nature, 282(5737), 378–383.
Choe,, J., Lin,, S., Zhang,, W., Liu,, Q., Wang,, L., Ramirez‐Moya,, J., … Gregory,, R. I. (2018). mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis. Nature, 561(7724), 556–560.
Clancy,, M. J., Shambaugh,, M. E., Timpte,, C. S., & Bokar,, J. A. (2002). Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6‐methyladenosine in mRNA: A potential mechanism for the activity of the IME4 gene. Nucleic Acids Research, 30(20), 4509–4518.
Dai,, Q., Fong,, R., Saikia,, M., Stephenson,, D., Yu,, Y.‐t., Pan,, T., & Piccirilli,, J. A. (2007). Identification of recognition residues for ligation‐based detection and quantitation of pseudouridine and N6‐methyladenosine. Nucleic Acids Research, 35(18), 6322–6329.
Deng,, X., Chen,, K., Luo,, G.‐Z., Weng,, X., Ji,, Q., Zhou,, T., & He,, C. (2015). Widespread occurrence of N6‐methyladenosine in bacterial mRNA. Nucleic Acids Research, 43(13), 6557–6567.
Desrosiers,, R., Friderici,, K., & Rottman,, F. (1974). Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proceedings of the National Academy of Sciences of the United States of America, 71(10), 3971–3975.
Dimock,, K., & Stoltzfus,, C. M. (1977). Sequence specificity of internal methylation in B77 avian sarcoma virus RNA subunits. Biochemistry, 16(3), 471–478.
Dominissini,, D., Moshitch‐Moshkovitz,, S., Schwartz,, S., Salmon‐Divon,, M., Ungar,, L., Osenberg,, S., … Rechavi,, G. (2012). Topology of the human and mouse m6A RNA methylomes revealed by m6A‐seq. Nature, 485(7397), 201–206.
Du,, Y., Hou,, G., Zhang,, H., Dou,, J., He,, J., Guo,, Y., … Yu,, J. (2018). SUMOylation of the m6A‐RNA methyltransferase METTL3 modulates its function. Nucleic Acids Research, 46(10), 5195–5208.
Fujita,, Y., Krause,, G., Scheffner,, M., Zechner,, D., Leddy,, H. E. M., Behrens,, J., … Birchmeier,, W. (2002). Hakai, a c‐Cbl‐like protein, ubiquitinates and induces endocytosis of the E‐cadherin complex [Article]. Nature Cell Biology, 4, 222–231.
Frye,, M., Harada,, B. T., Behm,, M., & He,, C. (2018). RNA modifications modulate gene expression during development. Science, 361(6409), 1346–1349.
Furuichi,, Y., Shatkin,, A. J., Stavnezer,, E., & Bishop,, J. M. (1975). Blocked, methylated 5′‐terminal sequence in avian sarcoma virus RNA. Nature, 257(5527), 618–620.
Garcia‐Campos,, M. A., Edelheit,, S., Toth,, U., Safra,, M., Shachar,, R., Viukov,, S., … Schwartz,, S. (2019). Deciphering the “m⁶A code” via antibody‐independent quantitative profiling. Cell, 178(3), 731‐747.e716.
Geula,, S., Moshitch‐Moshkovitz,, S., Dominissini,, D., Mansour,, A. A., Kol,, N., Salmon‐Divon,, M., … Hanna,, J. H. (2015). m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science, 347(6225), 1002–1006.
Gokhale,, N. S., McIntyre,, A. B. R., McFadden,, M. J., Roder,, A. E., Kennedy,, E. M., Gandara,, J. A., … Horner,, S. M. (2016). N6−Methyladenosine in Flaviviridae viral RNA genomes regulates infection. Cell Host %26 Microbe, 20(5), 654–665.
Guo,, J., Tang,, H.‐W., Li,, J., Perrimon,, N., & Yan,, D. (2018). Xio is a component of the Drosophila sex determination pathway and RNA N(6)‐methyladenosine methyltransferase complex. Proceedings of the National Academy of Sciences of the United States of America, 115(14), 3674–3679.
Harper,, J. E., Miceli,, S. M., Roberts,, R. J., & Manley,, J. L. (1990). Sequence specificity of the human mRNA N6‐adenosine methylase in vitro. Nucleic Acids Research, 18(19), 5735–5741.
Haussmann,, I. U., Bodi,, Z., Sanchez‐Moran,, E., Mongan,, N. P., Archer,, N., Fray,, R. G., & Soller,, M. (2016). m6A potentiates Sxl alternative pre‐mRNA splicing for robust Drosophila sex determination. Nature, 540(7632), 301–304.
Horiuchi,, K., Kawamura,, T., Iwanari,, H., Ohashi,, R., Naito,, M., Kodama,, T., & Hamakubo,, T. (2013). Identification of Wilms` tumor 1‐associating protein complex and its role in alternative splicing and the cell cycle. The Journal of Biological Chemistry, 288(46), 33292–33302.
Horowitz,, S., Horowitz,, A., Nilsen,, T. W., Munns,, T. W., & Rottman,, F. M. (1984). Mapping of N6‐methyladenosine residues in bovine prolactin mRNA. Proceedings of the National Academy of Sciences of the United States of America, 81(18), 5667–5671.
Huang,, H., Weng,, H., Zhou,, K., Wu,, T., Zhao,, B. S., Sun,, M., … Chen,, J. (2019). Histone H3 trimethylation at lysine 36 guides m6A RNA modification co‐transcriptionally. Nature, 567(7748), 414–419.
Huang,, J., Dong,, X., Gong,, Z., Qin,, L.‐Y., Yang,, S., Zhu,, Y.‐L., … Tang,, C. (2019). Solution structure of the RNA recognition domain of METTL3‐METTL14 N(6)‐methyladenosine methyltransferase. Protein %26 Cell, 10(4), 272–284.
Imam,, H., Khan,, M., Gokhale,, N. S., McIntyre,, A. B. R., Kim,, G.‐W., Jang,, J. Y., … Siddiqui,, A. (2018). N6−methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle. Proceedings of the National Academy of Sciences, 115(35), 8829.
Iyer,, L. M., Zhang,, D., & Aravind,, L. (2016). Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 38(1), 27–40.
Jia,, G., Fu,, Y., Zhao,, X., Dai,, Q., Zheng,, G., Yang,, Y., … He,, C. (2011). N6‐methyladenosine in nuclear RNA is a major substrate of the obesity‐associated FTO. Nature Chemical Biology, 7(12), 885–887.
Kang,, S., Han,, J. S., Kim,, K. P., Yang,, H. Y., Lee,, K. Y., Hong,, C. B., & Hwang,, D. S. (2005). Dimeric configuration of SeqA protein bound to a pair of hemi‐methylated GATC sequences. Nucleic Acids Research, 33(5), 1524–1531.
Kasowitz,, S. D., Ma,, J., Anderson,, S. J., Leu,, N. A., Xu,, Y., Gregory,, B. D., … Wang,, P. J. (2018). Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genetics, 14(5), e1007412.
Ke,, S., Pandya‐Jones,, A., Saito,, Y., Fak,, J. J., Vågbø,, C. B., Geula,, S., … Darnell,, R. B. (2017). m6A mRNA modifications are deposited in nascent pre‐mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes %26 Development, 31(10), 990–1006.
Knuckles,, P., Lence,, T., Haussmann,, I. U., Jacob,, D., Kreim,, N., Carl,, S. H., … Roignant,, J.‐Y. (2018). Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA‐binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes %26 Development, 32(5–6), 415–429.
Koh,, C. W. Q., Goh,, Y. T., & Goh,, W. S. S. (2019). Atlas of quantitative single‐base‐resolution N6‐methyl‐adenine methylomes. Nature Communications, 10(1), 5636.
Kowalak,, J. A., Dalluge,, J. J., McCloskey,, J. A., & Stetter,, K. O. (1994). The role of posttranscriptional modification in stabilization of transfer RNA from Hyperthermophiles. Biochemistry, 33(25), 7869–7876.
Lee,, J.‐H., & Skalnik,, D. G. (2012). Rbm15‐Mkl1 interacts with the Setd1b histone H3‐Lys4 methyltransferase via a SPOC domain that is required for cytokine‐independent proliferation. PLoS One, 7(8), e42965.
Lence,, T., Akhtar,, J., Bayer,, M., Schmid,, K., Spindler,, L., Ho,, C. H., … Roignant,, J.‐Y. (2016). m6A modulates neuronal functions and sex determination in Drosophila [Article]. Nature, 540(7632), 242–247.
Li,, H.‐B., Tong,, J., Zhu,, S., Batista,, P. J., Duffy,, E. E., Zhao,, J., … Flavell,, R. A. (2017). m(6)A mRNA methylation controls T cell homeostasis by targeting the IL‐7/STAT5/SOCS pathways. Nature, 548(7667), 338–342.
Lichinchi,, G., Zhao,, B. S., Wu,, Y., Lu,, Z., Qin,, Y., He,, C., & Rana,, T. M. (2016). Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host %26 Microbe, 20(5), 666–673.
Lin,, S., Choe,, J., Du,, P., Triboulet,, R., & Gregory,, R. I. (2016). METTL3 promotes translation in human cancer cells. Molecular Cell, 62(3), 335–345.
Lin,, Z., Hsu,, P. J., Xing,, X., Fang,, J., Lu,, Z., Zou,, Q., … Tong,, M.‐H. (2017). Mettl3−/Mettl14‐mediated mRNA N(6)‐methyladenosine modulates murine spermatogenesis. Cell Research, 27(10), 1216–1230.
Little,, N. A., Hastie,, N. D., & Davies,, R. C. (2000). Identification of WTAP, a novel Wilms` tumour 1‐associating protein. Human Molecular Genetics, 9(15), 2231–2239.
Liu,, J., Yue,, Y., Han,, D., Wang,, X., Fu,, Y., Zhang,, L., … He,, C. (2014). A METTL3‐METTL14 complex mediates mammalian nuclear RNA N6‐adenosine methylation. Nature Chemical Biology, 10(2), 93–95.
Louloupi,, A., Ntini,, E., Conrad,, T., & Ørom,, U. A. V. (2018). Transient N‐6‐methyladenosine transcriptome sequencing reveals a regulatory role of m6A in splicing efficiency. Cell Reports, 23(12), 3429–3437.
Lv,, J., Zhang,, Y., Gao,, S., Zhang,, C., Chen,, Y., Li,, W., … Liu,, F. (2018). Endothelial‐specific m(6)A modulates mouse hematopoietic stem and progenitor cell development via Notch signaling. Cell Research, 28(2), 249–252.
Ma,, H., Wang,, X., Cai,, J., Dai,, Q., Natchiar,, S. K., Lv,, R., … He,, C. (2019). N6‐Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nature Chemical Biology, 15(1), 88–94.
Ma,, Z., Morris,, S. W., Valentine,, V., L,, M., Herbrick,, J.‐A., Cui,, X., … Hitzler,, J. K. (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genetics, 28, 220–221.
Madhusoodanan,, U. K., & Rao,, D. N. (2010). Diversity of DNA methyltransferases that recognize asymmetric target sequences. Critical Reviews in Biochemistry and Molecular Biology, 45(2), 125–145.
Malovannaya,, A., Lanz,, R. B., Jung,, S. Y., Bulynko,, Y., Le,, N. T., Chan,, D. W., … Qin,, J. (2011). Analysis of the human endogenous coregulator complexome. Cell, 145(5), 787–799.
Machnicka,, M. A., Milanowska,, K., Osman Oglou,, O., Purta,, E., Kurkowska,, M., Olchowik,, A., … Grosjean,, H. (2013). MODOMICS: a database of RNA modification pathways. Nucleic acids research, 41, D262–D267.
Mauer,, J., Luo,, X., Blanjoie,, A., Jiao,, X., Grozhik,, A. V., Patil,, D. P., … Jaffrey,, S. R. (2017). Reversible methylation of m6Am in the 5′ cap controls mRNA stability [Article]. Nature, 541(7637), 371–375.
Mauer,, J., Sindelar,, M., Despic,, V., Guez,, T., Hawley,, B. R., Vasseur,, J.‐J., … Jaffrey,, S. R. (2019). FTO controls reversible m6Am RNA methylation during snRNA biogenesis. Nature Chemical Biology, 15(4), 340–347.
Meyer,, K. D., & Jaffrey,, S. R. (2016). Rethinking m6A readers, writers, and erasers. Annual Review of Cell and Developmental Biology.33, 319–342.
Meyer,, K. D., Saletore,, Y., Zumbo,, P., Elemento,, O., Mason,, C. E., & Jaffrey,, S. R. (2012). Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell, 149(7), 1635–1646.
Narayan,, P., & Rottman,, F. M. (1988). An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. Science, 242(4882), 1159–1162.
Nichols,, J. L. (1979). N6‐methyladenosine in maize poly(a)‐containing RNA. Plant Science Letters, 15(4), 357–361.
Ortega,, A., Niksic,, M., Bachi,, A., Wilm,, M., Sánchez,, L., Hastie,, N., & Valcárcel,, J. (2003). Biochemical function of female‐lethal (2)D/Wilms` tumor suppressor‐1‐associated proteins in alternative pre‐mRNA splicing. Journal of Biological Chemistry, 278(5), 3040–3047.
Patil,, D. P., Chen,, C.‐K., Pickering,, B. F., Chow,, A., Jackson,, C., Guttman,, M., & Jaffrey,, S. R. (2016). m(6)A RNA methylation promotes XIST‐mediated transcriptional repression. Nature, 537(7620), 369–373.
Pendleton,, K. E., Chen,, B., Liu,, K., Hunter,, O. V., Xie,, Y., Tu,, B. P., & Conrad,, N. K. (2017). The U6 snRNA m(6)A Methyltransferase METTL16 regulates SAM Synthetase intron retention. Cell, 169(5), 824–835 e814.
Perry,, R. P., & Kelley,, D. E. (1974). Existence of methylated messenger RNA in mouse L cells. Cell, 1(1), 37–42.
Ping,, X.‐L., Sun,, B.‐F., Wang,, L., Xiao,, W., Yang,, X., Wang,, W.‐J., … Yang,, Y.‐G. (2014). Mammalian WTAP is a regulatory subunit of the RNA N6‐methyladenosine methyltransferase [Original Article]. Cell Research, 24(2), 177–189.
Raffel,, G. D., Chu,, G. C., Jesneck,, J. L., Cullen,, D. E., Bronson,, R. T., Bernard,, O. A., & Gilliland,, D. G. (2009). Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Molecular and Cellular Biology, 29(2), 333–341.
Roundtree,, I. A., Luo,, G.‐Z., Zhang,, Z., Wang,, X., Zhou,, T., Cui,, Y., … He,, C. (2017). YTHDC1 mediates nuclear export of N6‐methyladenosine methylated mRNAs. eLife, 6, e31311.
Růžička,, K., Zhang,, M., Campilho,, A., Bodi,, Z., Kashif,, M., Saleh,, M., … Fray,, R. G. (2017). Identification of factors required for m6A mRNA methylation in Arabidopsis reveals a role for the conserved E3 ubiquitin ligase HAKAI. New Phytologist, 215(1), 157–172.
Schapira,, M. (2016). Structural chemistry of human RNA Methyltransferases. ACS Chemical Biology, 11(3), 575–582.
Schöller,, E., Weichmann,, F., Treiber,, T., Ringle,, S., Treiber,, N., Flatley,, A., … Meister,, G. (2018). Interactions, localization, and phosphorylation of the m(6)A generating METTL3‐METTL14‐WTAP complex. RNA (New York, N.Y.), 24(4), 499–512.
Schwartz,, S., Agarwala,, S. D., Mumbach,, M. R., Jovanovic,, M., Mertins,, P., Shishkin,, A., … Regev,, A. (2013). High‐resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell, 155(6), 1409–1421.
Schwartz,, S., Mumbach,, M. R., Jovanovic,, M., Wang,, T., Maciag,, K., Bushkin,, G. G., … Regev,, A. (2014). Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Reports, 8(1), 284–296.
Selberg,, S., Blokhina,, D., Aatonen,, M., Koivisto,, P., Siltanen,, A., Mervaala,, E., … Karelson,, M. (2019). Discovery of small molecules that activate RNA methylation through cooperative binding to the METTL3‐14‐WTAP complex active site. Cell Reports, 26(13), 3762–3771 e3765.
Shen,, L., Liang,, Z., Gu,, X., Chen,, Y., Teo,, Z. W. N., Hou,, X., … Yu,, H. (2016). N6‐Methyladenosine RNA modification regulates shoot stem cell fate in Arabidopsis. Developmental Cell, 38(2), 186–200.
Shi,, H., Wei,, J., & He,, C. (2019). Where, when, and how: Context‐dependent functions of RNA methylation writers, readers, and erasers. Molecular Cell, 74(4), 640–650.
Śledź,, P., & Jinek,, M. (2016). Structural insights into the molecular mechanism of the m6A writer complex. eLife, 5, e18434.
Slobodin,, B., Han,, R., Calderone,, V., Vrielink,, J. A. F. O., Loayza‐Puch,, F., Elkon,, R., & Agami,, R. (2017). Transcription impacts the efficiency of mRNA translation via co‐transcriptional N6‐adenosine methylation. Cell, 169(2), 326–337 e312.
Sommer,, S., Salditt‐Georgieff,, M., Bachenheimer,, S., Darnell,, J. E., Furuichi,, Y., Morgan,, M., & Shatkin,, A. J. (1976). Themethylation of adenovirus‐specific nuclear and cytoplasmic RNA. Nucleic Acids Research, 3(3), 749–765.
Sorci,, M., Ianniello,, Z., Cruciani,, S., Larivera,, S., Ginistrelli,, L. C., Capuano,, E., … Fatica,, A. (2018). METTL3 regulates WTAP protein homeostasis. Cell Death %26 Disease, 9(8), 796–796.
Tran,, N.‐T., Su,, H., Khodadadi‐Jamayran,, A., Lin,, S., Zhang,, L., Zhou,, D., … Zhao,, X. (2016). The AS‐RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Reports, 17(6), 887–900.
Wang,, P., Doxtader,, K. A., & Nam,, Y. (2016). Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Molecular Cell, 63(2), 306–317.
Wang,, X., Feng,, J., Xue,, Y., Guan,, Z., Zhang,, D., Liu,, Z., … Yin,, P. (2016). Structural basis of N6‐adenosine methylation by the METTL3–METTL14 complex [Letter]. Nature, 534(7608), 575–578.
Wang,, X., Lu,, Z., Gomez,, A., Hon,, G. C., Yue,, Y., Han,, D., … He,, C. (2014). N6‐methyladenosine‐dependent regulation of messenger RNA stability. Nature, 505(7481), 117–120.
Wang,, X., Lu,, Z., Gomez,, A., Hon,, G. C., Yue,, Y., Han,, D., … He, C. (2014). N6‐methyladenosine‐dependent regulation of messenger RNA stability. Nature, 505(7481), 117–120.
Wang,, X., Zhao,, B. S., Roundtree,, I. A., Lu,, Z., Han,, D., Ma,, H., … He,, C. (2015). N(6)‐methyladenosine modulates messenger RNA translation efficiency. Cell, 161(6), 1388–1399.
Wang,, Y., Li,, Y., Toth,, J. I., Petroski,, M. D., Zhang,, Z., & Zhao,, J. C. (2014). N6‐methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biology, 16(2), 191–198.
Wei,, C.‐M., Gershowitz,, A., & Moss,, B. (1975). Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA. Cell, 4(4), 379–386.
Wei,, C.‐M., & Moss,, B. (1977). Nucleotide sequences at the N6‐methyladenosine sites of HeLa cell messenger ribonucleic acid. Biochemistry, 16(8), 1672–1676.
Wen,, J., Lv,, R., Ma,, H., Shen,, H., He,, C., Wang,, J., … Diao,, J. (2018). Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self‐renewal. Molecular Cell, 69(6), 1028–1038.e1026.
Xiao,, W., Adhikari,, S., Dahal,, U., Chen,, Y.‐S., Hao,, Y.‐J., Sun,, B.‐F., … Yang,, Y. G. (2016). Nuclear m6A reader YTHDC1 regulates mRNA splicing. Molecular Cell, 61(4), 507–519.
Yan,, D., & Perrimon,, N. (2015). Spenito is required for sex determination in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America, 112(37), 11606–11611.
Yoon,, K.‐J., Ringeling,, F. R., Vissers,, C., Jacob,, F., Pokrass,, M., Jimenez‐Cyrus,, D., … Song,, H. (2017). Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell, 171(4), 877–889 e817.
Yue,, Y., Liu,, J., Cui,, X., Cao,, J., Luo,, G., Zhang,, Z., … Liu,, J. (2018). VIRMA mediates preferential m6A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation. Cell Discovery, 4(1), 10.
Zaccara,, S., Ries,, R. J., & Jaffrey,, S. R. (2019). Reading, writing and erasing mRNA methylation. Nature Reviews Molecular Cell Biology, 20(10), 608–624.
Zhang,, C., Chen,, Y., Sun,, B., Wang,, L., Yang,, Y., Ma,, D., … Liu,, F. (2017). m6A modulates haematopoietic stem and progenitor cell specification. Nature, 549, 273–276.
Zhao,, B. S., Roundtree,, I. A., & He,, C. (2017). Post‐transcriptional gene regulation by mRNA modifications. [Review]. Nature Reviews. Molecular Cell Biology, 18(1), 31–42.
Zheng,, G., Dahl,, J. A., Niu,, Y., Fedorcsak,, P., Huang,, C.‐M., Li,, C. J., … He,, C. (2013). ALKBH5 is a mammalian RNA Demethylase that impacts RNA metabolism and mouse fertility. Molecular Cell, 49(1), 18–29.
Zhong,, S., Li,, H., Bodi,, Z., Button,, J., Vespa,, L., Herzog,, M., & Fray,, R. G. (2008). MTA is an Arabidopsis messenger RNA adenosine Methylase and interacts with a homolog of a sex‐specific splicing factor. The Plant Cell, 20(5), 1278–1288.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

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

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox