RNA methyltransferase METTL16: Targets and function

Abstract

The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in the RNA modification landscape of the human cell. Originally thought to be a ribosomal RNA methyltransferase, it has now been shown to bind and methylate the MAT2A messenger RNA (mRNA) and U6 small nuclear RNA (snRNA). It has also been shown to bind the MALAT1 long noncoding RNA and several other RNAs. METTL16's methyltransferase domain contains the Rossmann-like fold of class I methyltransferases and uses S-adenosylmethionine (SAM) as the methyl donor. It has an RNA methylation consensus sequence of UACAGARAA (modified A underlined), and structural requirements for its known RNA interactors. In addition to the methyltransferase domain, METTL16 protein has two other RNA binding domains, one of which resides in a vertebrate conserved region, and a putative nuclear localization signal. The role of METTL16 in the cell is still being explored, however evidence suggests it is essential for most cells. This is currently hypothesized to be due to its role in regulating the splicing of MAT2A mRNA in response to cellular SAM levels. However, one of the more pressing questions remaining is what role METTL16's methylation of U6 snRNA plays in splicing and potentially cellular survival. METTL16 also has several other putative coding and noncoding RNA interactors but the definitive methylation status of those RNAs and the role METTL16 plays in their life cycle is yet to be determined. Overall, METTL16 is an intriguing RNA binding protein and methyltransferase whose important functions in the cell are just beginning to be understood. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.

Keywords: METTL16; N6-methyladenosine; RNA binding; RNA methyltransferase; epitranscriptomics.

FIGURE 1

Phylogenetic tree of METTL16 and homologs. Simple protein diagram of each organism's homolog and the protein name is located next to each respective species. Tree was generated using Seaview using distance methods under standard parameters (Gouy et al., 2010). Sizes of protein diagrams are approximate and not to scale

FIGURE 2

Schematic of human METTL16 protein. Numbers indicate amino acids from N to C terminals. RBD, N‐terminal RNA binding domain; VCR1, vertebrate conserved region 1; VCR2, vertebrate conserved region 2

FIGURE 3

Partial RNA structure of human lncRNA MALAT1 predicted to bind METTL16. Structure shows triple helix region where METTL16 is reported to interact. Asterisk indicates predicted m6A site. Adapted from Brown et al. (2012)

FIGURE 4

Partial RNA structures of human mRNA MAT2A 3′ UTR. The six hairpins are labeled relative to 5′ to 3′ direction. Nonamer sequence is highlighted, and asterisk indicates predicted m6A sites. Structures shown are when unbound to METTL16. Adapted from Parker et al. (2011)

FIGURE 5

Full RNA structure of human snRNA U6 predicted to bind METTL16. Numbered bases indicate 5′ to 3′ direction. Nonamer sequence is highlighted, and asterisk indicates m6A site (A43). Adapted from Aoyama et al. (2020)