N6-Methyladenosine

N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, and is an abundant modification in <a href="/facts/MRNA/oUL6qxQn">mRNA</a> and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. It is also found in <a href="/facts/TRNA/pR9T5XSl">tRNA</a>, <a href="/facts/RRNA/zy5FxddY">rRNA</a>, and <a href="/facts/Small_nuclear_RNA/6XKVBBJM">small nuclear RNA</a> (snRNA) as well as several <a href="/facts/Long_non-coding_RNA/FHyAb6hP">long non-coding RNA</a>, such as <a href="/facts/Xist/GgcYIt15">Xist</a>.
The <a href="/facts/Methylation/EvDMWVW5">methylation</a> of <a href="/facts/Adenosine/MwyTJ2wR">adenosine</a> is directed by a large m6A <a href="/facts/Methyltransferase/MIpCDLdh">methyltransferase</a> complex containing <a href="/facts/METTL3/jzETpN45">METTL3</a>, which is the subunit that binds <a href="/facts/S-adenosyl-L-methionine/oAsJ0SSR">S-adenosyl-L-methionine</a> (SAM). In vitro, this methyltransferase complex preferentially methylates RNA <a href="/facts/Oligonucleotides/Gc99fPnC">oligonucleotides</a> containing GGACU and a similar preference was identified in vivo in mapped m6A sites in <a href="/facts/Rous_sarcoma_virus/9oXl8G3N">Rous sarcoma virus</a> genomic RNA and in bovine <a href="/facts/Prolactin/NcdqrzFU">prolactin</a> mRNA. More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including <a href="/facts/METTL14/cBJo33jS">METTL14</a>, Wilms tumor 1 associated protein (<a href="/facts/WTAP_(gene)/D6KEB1kh">WTAP</a>), VIRMA and METTL5. Following a 2010 speculation of m6A in mRNA being dynamic and reversible, the discovery of the first m6A demethylase, fat mass and obesity-associated protein (<a href="/facts/FTO_gene/yIPpeM5H">FTO</a>) in 2011 confirmed this hypothesis and revitalized the interests in the study of m6A. A second m6A demethylase <a href="/facts/AlkB_homolog_5,_RNA_demethylase/qbGxjktK">alkB homolog 5</a> (ALKBH5) was later discovered as well.
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 <a href="/facts/YTH_protein_domain/I5pwXHQq">YT521-B homology (YTH) domain</a> family of proteins (<a href="/facts/YTHDF1/W7W4gCD2">YTHDF1</a>, <a href="/facts/YTHDF2/NCnVsbTs">YTHDF2</a>, <a href="/facts/YTHDF3/JoCLPDtH">YTHDF3</a> and <a href="/facts/YTHDC1/zS1avQwy">YTHDC1</a>) have been characterized as direct m6A readers and have a conserved m6A-binding pocket. Insulin-like growth factor-2 mRNA-binding proteins <a href="/facts/IGF2BP1/kB6LobyD">1</a>, <a href="/facts/IGF2BP2/olVY6dQ4">2</a>, and <a href="/facts/IGF2BP3/rpwB2g0B">3</a> (IGF2BP1–3) are reported as a novel class of m6A readers. IGF2BPs use <a href="/facts/KH_domain/VCNlgeeY">K homology (KH) domains</a> to selectively recognize m6A-containing RNAs and promote their translation and stability. 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. 
The specificity of m6A installation on mRNA is controlled by exon architecture and <a href="/facts/Exon_junction_complex/GRcTSQVh">exon junction complexes</a>. 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.

N6-Methyladenosine open-in-new

N6-Methyladenosine