6ma

N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, and is an abundant modification in mRNA and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.The methylation of adenosine is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit. In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA and in bovine prolactin mRNA. More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14, Wilms tumor 1 associated protein (WTAP), KIAA1429 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 (FTO) in 2011 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.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. Insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1–3) are reported as a novel class of m6A readers. IGF2BPs use K homology (KH) domains 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.

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