Human METTL16 is a N ⁶ ‐methyladenosine (m ⁶ A) methyltransferase that targets pre‐mRNAs and various non‐coding RNAs

Abstract

-methyladenosine (mA) is a highly dynamic RNA modification that has recently emerged as a key regulator of gene expression. While many mA modifications are installed by the METTL3-METTL14 complex, others appear to be introduced independently, implying that additional human mA methyltransferases remain to be identified. Using crosslinking and analysis of cDNA (CRAC), we reveal that the putative human mA "writer" protein METTL16 binds to the U6 snRNA and other ncRNAs as well as numerous lncRNAs and pre-mRNAs. We demonstrate that METTL16 is responsible for -methylation of A43 of the U6 snRNA and identify the early U6 biogenesis factors La, LARP7 and the methylphosphate capping enzyme MEPCE as METTL16 interaction partners. Interestingly, A43 lies within an essential ACAGAGA box of U6 that base pairs with 5' splice sites of pre-mRNAs during splicing, suggesting that METTL16-mediated modification of this site plays an important role in splicing regulation. The identification of METTL16 as an active mA methyltransferase in human cells expands our understanding of the mechanisms by which the mA landscape is installed on cellular RNAs.

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.…”

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

“…[8][9][10] In all classes of RNA, m6A mainly occurs within a highly-conserved consensus motif identified as RRACH (R=G or A, H=A, C or U). The formation of m6A is regulated by methyltransferases (METTL3, METTL14, WTAP, METTL16) 11,12 and demethylases (FTO, ALKBH5). 13,14 m6A recognizing proteins such as members of the YTH domain protein family and HNRNPA2B1 are involved in processes regulating the fate of target transcripts.…”

Pre‐mRNA modifications and their role in nuclear processing

“…One other human m 6 A methyltransferase, METTL16, was recently identified as the U6 snRNA methyltransferase with MAT2A as its only known direct mRNA methylation substrate. Consistent with its role in regulating MAT2A splicing [31] and in methylating the U6 snRNA [31,32], METTL16 was found to localize to the nucleus (Figure 1B) [33]. …”