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.

N6-Methyladenosine-Sculpted Regulatory Landscape of Noncoding RNA

“…In contrast to METTL3-METTL14-mediated m6A modification, METTL16 modified sites are primarily located in either introns or exonintron boundaries (49). METTL16 is responsible for the methylation of MAT2A mRNA and the spliceosome U6 snRNA (49,102,103,110). U6 snRNA is crucial to pre- mRNAs splicing events.…”

“…An enhanced abundance of m6A modification on XIST residues is mediated by RBM15/15B, which recruits the WTAP-METTL3 complex, and subsequently, YTHDC1 preferentially binds to m6A residues on XIST. Methyltransferase METTL16 can interact with lncRNA MALAT1, a cancer-related lncRNA (7,48,49). The crosslinking sites mainly occur at the 3' UTR of MALAT1, wherein the triple helix element is usually recruited.…”

“…These rRNAs m6A-modifications influence many aspects of ribosome activity, including localization, tertiary structure, and dynamics (109). In contrast to METTL3-METTL14-mediated m6A modification, METTL16 modified sites are primarily located in either introns or exonintron boundaries (49). METTL16 is responsible for the methylation of MAT2A mRNA and the spliceosome U6 snRNA (49,102,103,110).…”

The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

“…Indeed, METTL3 can catalyze the methylation modification of most mRNAs in vivo, and its homologue, METTL16 (methyltransferase-like protein 16), regulates the m 6 A modification of U6snRNA and a small fraction of mRNAs [ 46 , 47 ]. In addition, there are METTL5 (methyltransferase-like 5), ZCCHC4 (zinc finger CCHC-type containing 4), etc., which also have some catalytic functions for m 6 A on rRNAs [ 48 ].…”

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

“…METTL16 is a novel RNA methyltransferase that independently induces the m6A modification of the 3′UTR of mRNAs ( Satterwhite and Mansfield 2021 ), which have crucial roles in maintaining mRNA stability and splicing. M6A methyltransferases also display carcinogenic roles in several cancers.…”