METTL3/14 Complex (human, recombinant)

Methyltransferase-like protein 3 (METTL3) and METTL14 are m⁶A RNA methyltransferases encoded by the METTL3 and METTL14 genes, respectively, in humans.¹ METTL3 and METTL14 form a stable complex in the cytoplasm then localize to the nucleus via a METTL3 nuclear localization sequence. METTL3 contains an N-terminal leader helix domain that interacts with Wilms’ tumor 1-associated protein (WTAP) in the nucleus, which confers localization of the complex to nuclear speckles. METTL14 contains a C-terminal arginine-glycine-glycine (RGG) sequence that contributes to the catalytic activity of the complex. METTL3 and METTL14 each contain methyltransferase domains but the METTL3 domain alone binds S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) while METTL14 interacts with RNA.² The METTL3/14 complex primarily binds to regions of RNA that correspond to intergenic and intron regions of DNA, and it preferentially methylates RNA substrates that contain the sequence GGACU, with little preference for secondary structural features of the substrates.³ METTL3 and METTL14 are involved in hematopoietic stem cell differentiation in vitro and are necessary for self-renewal and reconstitution of hematopoietic stem cells following bone marrow transplantation in mice.⁴ Mettl3 knockdown or Mettl14 knockout increases radial glia cell cycle length in embryonic mouse brain, and Mettl14 knockout extends cortical neurogenesis into the postnatal period.⁵ Knockdown of METTL3 or METTL14 also increases proliferation of glioblastoma stem cells (GSCs) in vitro and increases tumor size in a mouse orthotopic model using GSCs.⁶ The expression of METTL3 and METTL14 is reduced in juvenile patients with ETV6/RUNX1(E/R)-positive acute lymphoblastic leukemia (ALL).⁷

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1. Scholler, E., Weichmann, F., Treiber, T., et al. Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex. RNA 24(4), 499-512 (2018).

2. Wang, P., Doxtader, K.A., and Nam, Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol. Cell 63(2), 306-317 (2016).

3. Liu, J., Yue, Y., Han, D., et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10(2), 93-95 (2014).

4. Yao, Q.J., Sang, L., Lin, M., et al. Mettl3-Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells. Cell Res. 28(9), 952-954 (2018).

5. Yoon, K.J., Ringeling, F.R., Vissers, C., et al. Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 171(4), 877-889 (2017).

6. Cui, Q., Shi, H., Ye, P., et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 18(11), 2622-2634 (2017).

7. Sun, C., Chang, L., Liu, C., et al. The study of METTL3 and METTL14 expressions in childhood ETV6/RUNX1-positive acute lymphoblastic leukemia. Mol. Genet. Genomic Med. 7(10), e00933 (2019).