Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification

Abstract

While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and counter‐restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, m6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m6A‐binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m6A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m6A demethylases, this proposal needs more careful evaluation.Also watch the Video Abstract.

Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

“…Sequence analysis suggests that Mettl3 catalytic site contains a more conserved DPPW motif, while Mettl14 has a more divergent EPPL sequence, which is not well conserved even within the Mettl14 family (Figure 2A) (Bujnicki et al, 2002; Iyer et al, 2016). When we compare the catalytic sites of MTD3 and MTD14 after structural superimposition, MTD3 has the more open cavity.…”

“…Mettl3 also forms stable complexes with Mettl14, which contains its own methyltransferase domain with a variant catalytic motif (Bujnicki et al, 2002; Liu et al, 2014; Wang et al, 2014a). Although isolated Mettl14 purified from insect cells was reported to have weak methyltransferase activity (Liu et al, 2014), phylogenetic studies of the active site motif suggests that it might have lost catalytic activity (Iyer et al, 2016). For normal m 6 A modification to occur in cells, Mettl3 and Mettl14 also need to associate with additional factors, such as Wilm's tumor 1-associated protein (WTAP), that may aid with proper localization (Ping et al, 2014; Schwartz et al, 2014).…”

The N‐terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation

“…Like METTL3 and METTL14, NRMT1 (METTL11A), and NRMT2 (METTL11B) are part of the Methyltransferase like (METTL) family of class I methyltransferases containing seven‐beta‐strand methyltransferase motifs and Rossman folds for binding SAM . Although the enzymes in the METTL family have a wide range of substrates, including protein, RNA, and small molecules, they are structurally similar .…”

“…Like METTL3 and METTL14, NRMT1 (METTL11A), and NRMT2 (METTL11B) are part of the Methyltransferase like (METTL) family of class I methyltransferases containing seven-beta-strand methyltransferase motifs and Rossman folds for binding SAM. 25,26 Although the enzymes in the METTL family have a wide range of substrates, including protein, RNA, and small molecules, they are structurally similar. 27 Given that METTL3 and METTL14 must form a heterodimer for optimal m 6 A methylation activity, 7 and NRMT1 has been shown to have increased N-terminal trimethylation activity when co-expressed with NRMT2, 14 we wanted to determine if NRMT1 and NRMT2 also heterodimerize.…”

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

“…In this complex, METTL3 constitutes the catalytic core and binds AdoMet but requires allosteric activation and stabilization by METTL14 (48,49). Although METTL14 has been reported to exhibit weak in vitro methylation activity (50), the phylogenetic analysis suggests that the METTL14 catalytic core has lost its function (51). In another example, mammalian PRMT7 and PRMT9 both harbor two catalytic modules in tandem, forming a pseudodimer.…”