The U6 snRNA m 6 A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Abstract

SUMMARY Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal snRNA. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

RNA m6A modification and its function in diseases

“…Therefore, the formation of specific m 6 A sites in specific mRNA might require distinct components of methyltransferase complex. This idea was further supported by the findings of METTL16 [30], which was shown to specifically form m 6 A in U6 snRNA and U6-like hairpins of MAT2A mRNA in a C-m A residues in RNAs were found to be real substrates of FTO in vitro. This study was first to indicate that the ubiquitously distributed m 6 A modifications on mRNA might be reversely regulated by methyltransferases and demethylases, thereby serving as a previously unappreciated layer of regulation on mRNAs.…”

“…m 6 A facilitated the binding of a splicing regulator, HNRNPC, to its targets by m 6 A-induced structural switch [63]. Similarly, the m 6 A, specifically catalyzed by METTL16 in the hairpins of MAT2A pre-mRNAs, was required for the splicing of this intron [30]. Furthermore, depletion of m 6 A reader protein YTHDC1 caused splicing abnormalities, which could only be resolved by YTH domain-containing YTHDC1 proteins [64].…”

N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

“…This indicates that in our RNA pulldowns we identified both direct RNA-protein interactors and indirect RNA-protein interactors, which are mediated by protein-protein interactions. Another repelled protein is METTL16, which was very recently identified as an adenosine methyltransferase for small nuclear RNA 36 . GO-term enrichment analysis of proteins that are repelled by m 6 A revealed terms related to mRNA splicing and transport (Fig.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…demonstrated two previously unrecognized components of the m 6 A methylation complex, namely RNA‐binding motif protein 15 (RBM15) and its paralogue RBM15B, in 2016 24. And METTL16 is also regarded as the methyltransferase that modifies U6 snRNAs and various non‐coding RNAs 25, 26. To date, the supposed core component of m 6 A methyltransferase is METTL3‐METTL14‐WTAP‐VIRMA‐HAKAI‐ZC3H13.…”