N6-Methyladenosine

N6-Methyladenosine
Names
IUPAC name
N6-Methyladenosine
Systematic IUPAC name
(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-[6-(methylamino)-9H-purin-9-yl]oxolane-2,3-diol
Other names
m6A
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C11H15N5O4/c1-12-9-6-10(14-3-13-9)16(4-15-6)11-8(19)7(18)5(2-17)20-11/h3-5,7-8,11,17-19H,2H2,1H3,(H,12,13,14)/t5-,7-,8-,11-/m1/s1
    Key: VQAYFKKCNSOZKM-IOSLPCCCSA-N
  • n2c1c(ncnc1NC)n(c2)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO
Properties
C11H15N5O4
Molar mass 281.272 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s,[1][2][3][4] and is an abundant modification in mRNA and DNA.[5] It is found within some viruses,[4][3][6][7] and most eukaryotes including mammals,[2][1][8][9] insects,[10] plants[11][12][13] and yeast.[14][15] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.[16][17]

The methylation of adenosine is directed by a large m6A methyltransferase complex containing METTL3, which is the subunit that binds S-adenosyl-L-methionine (SAM).[18] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU[19] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA[20] and in bovine prolactin mRNA.[21] More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14,[22][23] Wilms tumor 1 associated protein (WTAP),[22][24] VIRMA[25] and METTL5.[26] Following a 2010 speculation of m6A in mRNA being dynamic and reversible,[27] the discovery of the first m6A demethylase, fat mass and obesity-associated protein (FTO) in 2011[28] confirmed this hypothesis and revitalized the interests in the study of m6A. A second m6A demethylase alkB homolog 5 (ALKBH5) was later discovered as well.[29]

The biological functions of m6A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m6A readers. The YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3 and YTHDC1) have been characterized as direct m6A readers and have a conserved m6A-binding pocket.[17][30][31][32][33] Insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1–3) are reported as a novel class of m6A readers.[34] IGF2BPs use K homology (KH) domains to selectively recognize m6A-containing RNAs and promote their translation and stability.[34] These m6A readers, together with m6A methyltransferases (writers) and demethylases (erasers), establish a complex mechanism of m6A regulation in which writers and erasers determine the distributions of m6A on RNA, whereas readers mediate m6A-dependent functions. m6A has also been shown to mediate a structural switch termed m6A switch.[35]

The specificity of m6A installation on mRNA is controlled by exon architecture and exon junction complexes. Exon junction complexes suppress m6A methylation near exon-exon junctions by packaging nearby RNA and protecting it from methylation by the m6A methyltransferase complex. m6A regions in long internal and terminal exons, away from exon-exon junctions and exon junction complexes, escape suppression and can be methylated by the methyltransferase complex. [36]

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